Skip to content
2000
Volume 32, Issue 28
  • ISSN: 0929-8673
  • E-ISSN: 1875-533X

Abstract

A new pharmacotherapy prescribed by medical oncology professionals for breast cancer patients emerged at the end of last year. Capivasertib is the first approved inhibitor targeting protein kinase B (Akt), and has been manufactured as the active ingredient in the oral medicine TruqapTM. This compound has joined the prestigious list of successful pharmacological agents that were discovered by exploiting a fruitful medicinal chemistry paradigm named fragment-based drug design. In this article, we provide a brief theoretical basis for this strategy and present a speculative overview of the experimental and computational workflows involved in the discovery of this small-molecule antitumor drug, highlighting some of the details of its rational design, which were crucial to the success of the campaign, and culminated in the recent approval of the seventh magic bullet derived from molecular fragments.

© 2025 Bentham Science Publishers
Loading

Article metrics loading...

/content/journals/cmc/10.2174/0109298673331253241004110953
2025-03-26
2025-09-06

  • From This Site

    /content/journals/cmc/10.2174/0109298673331253241004110953
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

References

  1. JencksW.P. On the attribution and additivity of binding energies.Proc. Natl. Acad. Sci. USA19817874046405010.1073/pnas.78.7.404616593049
     [Google Scholar]
  2. ShukerS.B. HajdukP.J. MeadowsR.P. FesikS.W. Discovering high-affinity ligands for proteins: SAR by NMR.Science199627452921531153410.1126/science.274.5292.15318929414
     [Google Scholar]
  3. KonteatisZ. What makes a good fragment in fragment-based drug discovery?Expert Opin. Drug Discov.202116772372610.1080/17460441.2021.190562933769176
     [Google Scholar]
  4. CongreveM. CarrR. MurrayC. JhotiH. A ‘Rule of Three’ for fragment-based lead discovery?Drug Discov. Today200381987687710.1016/S1359‑6446(03)02831‑914554012
     [Google Scholar]
  5. LipinskiC.A. LombardoF. DominyB.W. FeeneyP.J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings.Adv. Drug Deliv. Rev.2001461-332610.1016/S0169‑409X(00)00129‑011259830
     [Google Scholar]
  6. OwensJ. Chris Lipinski discusses life and chemistry after the Rule of Five.Drug Discov. Today200381121610.1016/S1359‑6446(02)02556‑412546981
     [Google Scholar]
  7. JhotiH. WilliamsG. ReesD.C. MurrayC.W. The ‘rule of three’ for fragment-based drug discovery: Where are we now?Nat. Rev. Drug Discov.201312864464510.1038/nrd3926‑c123845999
     [Google Scholar]
  8. BonM. BilslandA. BowerJ. McAulayK. Fragment-based drug discovery—the importance of high-quality molecule libraries.Mol. Oncol.202216213761377710.1002/1878‑0261.1327735749608
     [Google Scholar]
  9. CarberyA. SkynerR. von DelftF. DeaneC.M. Fragment libraries designed to be functionally diverse recover protein binding information more efficiently than standard structurally diverse libraries.J. Med. Chem.20226516114041141310.1021/acs.jmedchem.2c0100435960886
     [Google Scholar]
  10. HamiltonD.J. DekkerT. KleinH.F. JanssenG.V. WijtmansM. O’BrienP. de EschI.J.P. Escape from planarity in fragment-based drug discovery: A physicochemical and 3D property analysis of synthetic 3D fragment libraries.Drug Discov. Today. Technol.202038779010.1016/j.ddtec.2021.05.00134895643
     [Google Scholar]
  11. HopkinsA.L. GroomC.R. AlexA. Ligand efficiency: A useful metric for lead selection.Drug Discov. Today200491043043110.1016/S1359‑6446(04)03069‑715109945
     [Google Scholar]
  12. LiQ. Application of fragment-based drug discovery to versatile targets.Front. Mol. Biosci.2020718010.3389/fmolb.2020.0018032850968
     [Google Scholar]
  13. HopkinsA.L. KeserüG.M. LeesonP.D. ReesD.C. ReynoldsC.H. The role of ligand efficiency metrics in drug discovery.Nat. Rev. Drug Discov.201413210512110.1038/nrd416324481311
     [Google Scholar]
  14. PolanskiJ. PedrysA. DuszkiewiczR. KuciaU. Ligand potency, efficiency and drug-likeness: a story of intuition, misinterpretation and serendipity.Curr. Protein Pept. Sci.201920111069107610.2174/138920371966619052708083231131749
     [Google Scholar]
  15. VerdonkM.L. ReesD.C. Group efficiency: A guideline for hits-to-leads chemistry.ChemMedChem2008381179118010.1002/cmdc.20080013218651625
     [Google Scholar]
  16. ShulgaD.A. IvanovN.N. PalyulinV.A. In silico structure-based approach for group efficiency estimation in fragment-based drug design using evaluation of fragment contributions.Molecules2022276198510.3390/molecules2706198535335347
     [Google Scholar]
  17. MurrayC.W. ErlansonD.A. HopkinsA.L. KeserüG.M. LeesonP.D. ReesD.C. ReynoldsC.H. RichmondN.J. Validity of ligand efficiency metrics.ACS Med. Chem. Lett.20145661661810.1021/ml500146d24944729
     [Google Scholar]
  18. LeesonP.D. BentoA.P. GaultonA. HerseyA. MannersE.J. RadouxC.J. LeachA.R. Target-based evaluation of “drug-like” properties and ligand efficiencies.J. Med. Chem.202164117210723010.1021/acs.jmedchem.1c0041633983732
     [Google Scholar]
  19. PolanskiJ. BakA. Ligand potency - An essential estimator for drug design: between intuition, misinterpretation and serendipity.Future Med. Chem.201911141827184310.4155/fmc‑2018‑023031304827
     [Google Scholar]
  20. PolanskiJ. PedrysA. DuszkiewiczR. GasteigerJ. Scoring ligand efficiency: Potency, ligand efficiency and product ligand efficiency within big data landscape.Lett. Drug Des. Discov.201916111258126310.2174/1570180816666190112154505
     [Google Scholar]
  21. MinettiC.A. RemetaD.P. Forces driving a magic bullet to its target: Revisiting the role of thermodynamics in drug design, development, and optimization.Life (Basel)2022129143810.3390/life1209143836143474
     [Google Scholar]
  22. LiQ. KangC. Perspectives on fragment-based drug discovery: A strategy applicable to diverse targets.Curr. Top. Med. Chem.202121131099111210.2174/156802662166621080411570034348623
     [Google Scholar]
  23. GozalbesR. CarbajoR.J. Pineda-LucenaA. Contributions of computational chemistry and biophysical techniques to fragment-based drug discovery.Curr. Med. Chem.201017171769179410.2174/09298671079111122420345344
     [Google Scholar]
  24. ErlansonD.A. FesikS.W. HubbardR.E. JahnkeW. JhotiH. Twenty years on: The impact of fragments on drug discovery.Nat. Rev. Drug Discov.201615960561910.1038/nrd.2016.10927417849
     [Google Scholar]
  25. ShiY. von ItzsteinM. How size matters: Diversity for fragment library design.Molecules20192415283810.3390/molecules2415283831387220
     [Google Scholar]
  26. TroelsenN.S. ClausenM.H. Library design strategies to accelerate fragment-based drug discovery.Chemistry20202650113911140310.1002/chem.20200058432339336
     [Google Scholar]
  27. WangZ.Z. ShiX.X. HuangG.Y. HaoG.F. YangG.F. Fragment-based drug design facilitates selective kinase inhibitor discovery.Trends Pharmacol. Sci.202142755156510.1016/j.tips.2021.04.00133958239
     [Google Scholar]
  28. ChenH. ZhouX. WangA. ZhengY. GaoY. ZhouJ. Evolutions in fragment-based drug design: The deconstruction–reconstruction approach.Drug Discov. Today201520110511310.1016/j.drudis.2014.09.01525263697
     [Google Scholar]
  29. KeserűG.M. ErlansonD.A. FerenczyG.G. HannM.M. MurrayC.W. PickettS.D. Design principles for fragment libraries: Maximizing the value of learnings from pharma fragment-based drug discovery (FBDD) programs for use in academia.J. Med. Chem.201659188189820610.1021/acs.jmedchem.6b0019727124799
     [Google Scholar]
  30. BedwellE.V. McCarthyW.J. CoyneA.G. AbellC. Development of potent inhibitors by fragment-linking strategies.Chem. Biol. Drug Des.2022100446948610.1111/cbdd.1412035854428
     [Google Scholar]
  31. BancetA. RaingevalC. LombergetT. Le BorgneM. GuichouJ.F. KrimmI. Fragment linking strategies for structure-based drug design.J. Med. Chem.20206320114201143510.1021/acs.jmedchem.0c0024232539387
     [Google Scholar]
  32. KumarA. VoetA. ZhangK.Y.J. Fragment based drug design: From experimental to computational approaches.Curr. Med. Chem.201219305128514710.2174/09298671280353046722934764
     [Google Scholar]
  33. BianY. XieX.Q. Computational fragment-based drug design: Current trends, strategies, and applications.AAPS J.20182035910.1208/s12248‑018‑0216‑729633051
     [Google Scholar]
  34. KirschP. HartmanA.M. HirschA.K.H. EmptingM. Concepts and core principles of fragment-based drug design.Molecules20192423430910.3390/molecules2423430931779114
     [Google Scholar]
  35. RenaudJ.P. ChungC. DanielsonU.H. EgnerU. HennigM. HubbardR.E. NarH. Biophysics in drug discovery: Impact, challenges and opportunities.Nat. Rev. Drug Discov.2016151067969810.1038/nrd.2016.12327516170
     [Google Scholar]
  36. ChenP. LiQ. LeiX. Review of the impact of fragment-based drug design on PROTAC degrader discovery.Trends Analyt. Chem.202417111753911753910.1016/j.trac.2024.117539
     [Google Scholar]
  37. SabeV.T. NtombelaT. JhambaL.A. MaguireG.E.M. GovenderT. NaickerT. KrugerH.G. Current trends in computer aided drug design and a highlight of drugs discovered via computational techniques: A review.Eur. J. Med. Chem.202122411370511370510.1016/j.ejmech.2021.11370534303871
     [Google Scholar]
  38. ChangY. HawkinsB.A. DuJ.J. GroundwaterP.W. HibbsD.E. LaiF. A guide to in silico drug design.Pharmaceutics20221514910.3390/pharmaceutics1501004936678678
     [Google Scholar]
  39. SadybekovA.V. KatritchV. Computational approaches streamlining drug discovery.Nature2023616795867368510.1038/s41586‑023‑05905‑z37100941
     [Google Scholar]
  40. EliasT.C. de OliveiraH.C.B. da SilveiraN.J.F. MB-Isoster: A software for bioisosterism simulation.J. Comput. Chem.201839292481248710.1002/jcc.2558130318630
     [Google Scholar]
  41. BorbaJ.R.B.M. de AraújoL.P. VelosoM.P. da SilveiraN.J.F. Applying the bioisosterism strategy to obtain lead compounds against SARS-CoV-2 cysteine proteases: An in-silico approach.J. Comput. Chem.2024451354610.1002/jcc.2721737641955
     [Google Scholar]
  42. Bitencourt-FerreiraG. de AzevedoW.F.Jr. How docking programs work.Docking Screens for Drug DiscoveryHumanaNew York2019355010.1007/978‑1‑4939‑9752‑7_3
     [Google Scholar]
  43. JakharR. DangiM. KhichiA. ChhillarA.K. Relevance of molecular docking studies in drug designing.Curr. Bioinform.202015427027810.2174/1574893615666191219094216
     [Google Scholar]
  44. GuptaS. BawejaG.S. SinghS. IraniM. SinghR. AsatiV. Integrated fragment-based drug design and virtual screening techniques for exploring the antidiabetic potential of thiazolidine-2,4-diones: Design, synthesis and in vivo studies.Eur. J. Med. Chem.202326111582611582610.1016/j.ejmech.2023.11582637793328
     [Google Scholar]
  45. SaikiaS. BordoloiM. Molecular docking: Challenges, advances and its use in drug discovery perspective.Curr. Drug Targets201920550152110.2174/138945011966618102215301630360733
     [Google Scholar]
  46. Bitencourt-FerreiraG. de AzevedoW.F.Jr. SAnDReS: A computational tool for docking.Docking Screens for Drug DiscoveryHumanaNew York2019516510.1007/978‑1‑4939‑9752‑7_4
     [Google Scholar]
  47. Bitencourt-FerreiraG. RizzottoC. de Azevedo JuniorW.F. Machine learning-based scoring functions, development and applications with SAnDReS.Curr. Med. Chem.20212891746175610.2174/1875533XMTA25NjQu432410551
     [Google Scholar]
  48. XavierM.M. HeckG.S. de AvilaM.B. LevinN.M.B. PintroV.O. CarvalhoN.L. de AzevedoW.F. SAnDReS a computational tool for statistical analysis of docking results and development of scoring functions.Comb. Chem. High Throughput Screen.2016191080181210.2174/138620731966616092711134727686428
     [Google Scholar]
  49. de AzevedoW.F.Junior Bitencourt-FerreiraG. VillarrealM.A. QuirogaR. BiziukovaN. PoroikovV. TarasovaO. Exploring scoring function space: Developing computational models for drug discovery.Curr. Med. Chem.202431172361237710.2174/0929867330666230321103731
     [Google Scholar]
  50. TrottO. OlsonA.J. AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading.J. Comput. Chem.201031245546110.1002/jcc.2133419499576
     [Google Scholar]
  51. KuntzI.D. BlaneyJ.M. OatleyS.J. LangridgeR. FerrinT.E. A geometric approach to macromolecule-ligand interactions.J. Mol. Biol.1982161226928810.1016/0022‑2836(82)90153‑X7154081
     [Google Scholar]
  52. GoossensK. WroblowskiB. LanginiC. van VlijmenH. CaflischA. De WinterH. Assessment of the fragment docking program SEED.J. Chem. Inf. Model.202060104881489310.1021/acs.jcim.0c0055632820916
     [Google Scholar]
  53. GrosdidierA. ZoeteV. MichielinO. SwissDock, a protein-small molecule docking web service based on EADock DSS.Nucleic Acids Res.201139Web Server issueW270W27710.1093/nar/gkr36621624888
     [Google Scholar]
  54. Bitencourt-FerreiraG. de AzevedoW.F. Docking with SwissDock.Docking Screens for Drug DiscoveryHumanaNew York201918920210.1007/978‑1‑4939‑9752‑7_12
     [Google Scholar]
  55. ArgusLab.Available from: http://www.arguslab.com/arguslab.com/ArgusLab.html (Accessed on: April 23, 2024).
  56. Bitencourt-FerreiraG. de AzevedoW.F. Molecular docking simulations with ArgusLab.Docking Screens for Drug DiscoveryNew YorkHumana201920322010.1007/978‑1‑4939‑9752‑7_13
     [Google Scholar]
  57. ThomsenR. ChristensenM.H. MolDock: A new technique for high-accuracy molecular docking.J. Med. Chem.200649113315332110.1021/jm051197e16722650
     [Google Scholar]
  58. Bitencourt-FerreiraG. de AzevedoW.F.Jr. Molegro virtual docker for docking.Docking Screens for Drug DiscoveryHumanaNew York201914916710.1007/978‑1‑4939‑9752‑7_10
     [Google Scholar]
  59. KramerB. RareyM. LengauerT. Evaluation of the FLEXX incremental construction algorithm for protein-ligand docking.Proteins199937222824110584068
     [Google Scholar]
  60. FriesnerR.A. BanksJ.L. MurphyR.B. HalgrenT.A. KlicicJ.J. MainzD.T. RepaskyM.P. KnollE.H. ShelleyM. PerryJ.K. ShawD.E. FrancisP. ShenkinP.S. Glide: A new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy.J. Med. Chem.20044771739174910.1021/jm030643015027865
     [Google Scholar]
  61. VerdonkM.L. ColeJ.C. HartshornM.J. MurrayC.W. TaylorR.D. Improved protein–ligand docking using GOLD.Proteins200352460962310.1002/prot.1046512910460
     [Google Scholar]
  62. ErlansonD.A. DavisB.J. JahnkeW. Fragment-based drug discovery: Advancing fragments in the absence of crystal structures.Cell Chem. Biol.201926191510.1016/j.chembiol.2018.10.00130482678
     [Google Scholar]
  63. KuanJ. RadaevaM. AvenidoA. CherkasovA. GentileF. Keeping pace with the explosive growth of chemical libraries with structure-based virtual screening.Wiley Interdiscip. Rev. Comput. Mol. Sci.2023136e167810.1002/wcms.1678
     [Google Scholar]
  64. SadybekovA.A. SadybekovA.V. LiuY. Iliopoulos-TsoutsouvasC. HuangX.P. PickettJ. HouserB. PatelN. TranN.K. TongF. ZvonokN. JainM.K. SavychO. RadchenkoD.S. NikasS.P. PetasisN.A. MorozY.S. RothB.L. MakriyannisA. KatritchV. Synthon-based ligand discovery in virtual libraries of over 11 billion compounds.Nature2022601789345245910.1038/s41586‑021‑04220‑934912117
     [Google Scholar]
  65. ZhengB.F. WangZ.Z. DongJ. MaJ.Y. ZuoY. WuQ.Y. YangG.F. Discovery of a subnanomolar inhibitor of protoporphyrinogen ix oxidase via fragment-based virtual screening.J. Agric. Food Chem.202371238746875610.1021/acs.jafc.3c0016837261811
     [Google Scholar]
  66. KaplanA.L. ConfairD.N. KimK. Barros-ÁlvarezX. RodriguizR.M. YangY. KweonO.S. CheT. McCorvyJ.D. KamberD.N. PhelanJ.P. MartinsL.C. PogorelovV.M. DiBertoJ.F. SlocumS.T. HuangX.P. KumarJ.M. RobertsonM.J. PanovaO. SevenA.B. WetselA.Q. WetselW.C. IrwinJ.J. SkiniotisG. ShoichetB.K. RothB.L. EllmanJ.A. Bespoke library docking for 5-HT2A receptor agonists with antidepressant activity.Nature2022610793258259110.1038/s41586‑022‑05258‑z36171289
     [Google Scholar]
  67. MandalM. XiaoL. PanW. ScapinG. LiG. TangH. YangS.W. PanJ. RootY. de JesusR.K. YangC. ProsiseW. DayananthP. MirzaA. TherienA.G. YoungK. FlatteryA. GarlisiC. ZhangR. ChuD. ShethP. ChuI. WuJ. MarkgrafC. KimH.Y. PainterR. MayhoodT.W. DiNunzioE. WyssD.F. BuevichA.V. FischmannT. PasternakA. DongS. HicksJ.D. VillafaniaA. LiangL. MurgoloN. BlackT. HagmannW.K. TataJ. ParmeeE.R. WeberA.E. SuJ. TangH. Rapid evolution of a fragment-like molecule to pan-metallo-beta-lactamase inhibitors: Initial leads toward clinical candidates.J. Med. Chem.20226524162341625110.1021/acs.jmedchem.2c0076636475645
     [Google Scholar]
  68. TurnerL.D. TrinhC.H. HubballR.A. OrrittK.M. LinC.C. BurnsJ.E. KnowlesM.A. FishwickC.W.G. From fragment to lead: De novo design and development toward a selective fgfr2 inhibitor.J. Med. Chem.20226521481150410.1021/acs.jmedchem.1c0116334780700
     [Google Scholar]
  69. LuttensA. GullbergH. AbdurakhmanovE. VoD.D. AkaberiD. TalibovV.O. NekhotiaevaN. VangeelL. De JongheS. JochmansD. KrambrichJ. TasA. LundgrenB. GravenforsY. CraigA.J. AtilawY. SandströmA. MoodieL.W.K. LundkvistÅ. van HemertM.J. NeytsJ. LennerstrandJ. KihlbergJ. SandbergK. DanielsonU.H. CarlssonJ. Ultralarge virtual screening identifies SARS-COV-2 main protease inhibitors with broad-spectrum activity against coronaviruses.J. Am. Chem. Soc.202214472905292010.1021/jacs.1c0840235142215
     [Google Scholar]
  70. RomasantaA.K.S. van der SijdeP. HellstenI. HubbardR.E. KeseruG.M. van Muijlwijk-KoezenJ. de EschI.J.P. When fragments link: A bibliometric perspective on the development of fragment-based drug discovery.Drug Discov. Today20182391596160910.1016/j.drudis.2018.05.00429738823
     [Google Scholar]
  71. WoodheadA.J. ErlansonD.A. de EschI.J.P. HolveyR.S. JahnkeW. PathuriP. Fragment-to-lead medicinal chemistry publications in 2022.J. Med. Chem.20246742287230410.1021/acs.jmedchem.3c0207038289623
     [Google Scholar]
  72. Fragments vs. herpesviridae.2024Available from: https://practicalfragments.blogspot.com/2024/02/fragments-in-clinic-2024-edition.html (Accessed on: April 23, 2024).
  73. SantosL.M. da SilveiraN.J.F. Fragment-based drug discovery successful contributions to current pharmacotherapeutic agents arsenal against aggressive cancers: A mini-review.Anticancer. Agents Med. Chem.202323161796181010.2174/187152062366623071416382337455450
     [Google Scholar]
  74. TsaiJ. LeeJ.T. WangW. ZhangJ. ChoH. MamoS. BremerR. GilletteS. KongJ. HaassN.K. SproesserK. LiL. SmalleyK.S.M. FongD. ZhuY.L. MarimuthuA. NguyenH. LamB. LiuJ. CheungI. RiceJ. SuzukiY. LuuC. SettachatgulC. ShellooeR. CantwellJ. KimS.H. SchlessingerJ. ZhangK.Y.J. WestB.L. PowellB. HabetsG. ZhangC. IbrahimP.N. HirthP. ArtisD.R. HerlynM. BollagG. Discovery of a selective inhibitor of oncogenic B-Raf kinase with potent antimelanoma activity.Proc. Natl. Acad. Sci. USA200810583041304610.1073/pnas.071174110518287029
     [Google Scholar]
  75. SouersA.J. LeversonJ.D. BoghaertE.R. AcklerS.L. CatronN.D. ChenJ. DaytonB.D. DingH. EnschedeS.H. FairbrotherW.J. HuangD.C.S. HymowitzS.G. JinS. KhawS.L. KovarP.J. LamL.T. LeeJ. MaeckerH.L. MarshK.C. MasonK.D. MittenM.J. NimmerP.M. OleksijewA. ParkC.H. ParkC.M. PhillipsD.C. RobertsA.W. SampathD. SeymourJ.F. SmithM.L. SullivanG.M. TahirS.K. TseC. WendtM.D. XiaoY. XueJ.C. ZhangH. HumerickhouseR.A. RosenbergS.H. ElmoreS.W. ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets.Nat. Med.201319220220810.1038/nm.304823291630
     [Google Scholar]
  76. PereraT.P.S. JovchevaE. MevellecL. VialardJ. De LangeD. VerhulstT. PaulussenC. Van De VenK. KingP. FreyneE. ReesD.C. SquiresM. SaxtyG. PageM. MurrayC.W. GilissenR. WardG. ThompsonN.T. NewellD.R. ChengN. XieL. YangJ. PlateroS.J. KarkeraJ.D. MoyC. AngibaudP. LaquerreS. LorenziM.V. Discovery and pharmacological characterization of jnj-42756493 (erdafitinib), a functionally selective small-molecule FGFR family inhibitor.Mol. Cancer Ther.20171661010102010.1158/1535‑7163.MCT‑16‑058928341788
     [Google Scholar]
  77. TapW.D. WainbergZ.A. AnthonyS.P. IbrahimP.N. ZhangC. HealeyJ.H. ChmielowskiB. StaddonA.P. CohnA.L. ShapiroG.I. KeedyV.L. SinghA.S. PuzanovI. KwakE.L. WagnerA.J. Von HoffD.D. WeissG.J. RamanathanR.K. ZhangJ. HabetsG. ZhangY. BurtonE.A. VisorG. SanftnerL. SeversonP. NguyenH. KimM.J. MarimuthuA. TsangG. ShellooeR. GeeC. WestB.L. HirthP. NolopK. van de RijnM. HsuH.H. PeterfyC. LinP.S. Tong-StarksenS. BollagG. Structure-guided blockade of CSF1R kinase in tenosynovial giant-cell tumor.N. Engl. J. Med.2015373542843710.1056/NEJMoa141136626222558
     [Google Scholar]
  78. LanmanB.A. AllenJ.R. AllenJ.G. AmegadzieA.K. AshtonK.S. BookerS.K. ChenJ.J. ChenN. FrohnM.J. GoodmanG. KopeckyD.J. LiuL. LopezP. LowJ.D. MaV. MinattiA.E. NguyenT.T. NishimuraN. PickrellA.J. ReedA.B. ShinY. SiegmundA.C. TamayoN.A. TegleyC.M. WaltonM.C. WangH.L. WurzR.P. XueM. YangK.C. AchantaP. BartbergerM.D. CanonJ. HollisL.S. McCarterJ.D. MohrC. RexK. SaikiA.Y. San MiguelT. VolakL.P. WangK.H. WhittingtonD.A. ZechS.G. LipfordJ.R. CeeV.J. Discovery of a covalent inhibitor of KRASG12C (AMG 510) for the treatment of solid tumors.J. Med. Chem.2020631526510.1021/acs.jmedchem.9b0118031820981
     [Google Scholar]
  79. SchoepferJ. JahnkeW. BerelliniG. BuonamiciS. CotestaS. Cowan-JacobS.W. DoddS. DrueckesP. FabbroD. GabrielT. GroellJ.M. GrotzfeldR.M. HassanA.Q. HenryC. IyerV. JonesD. LombardoF. LooA. ManleyP.W. PelléX. RummelG. SalemB. WarmuthM. WylieA.A. ZollerT. MarzinzikA.L. FuretP. Discovery of Asciminib (ABL001), an allosteric inhibitor of the tyrosine kinase activity of BCR-ABL1.J. Med. Chem.201861188120813510.1021/acs.jmedchem.8b0104030137981
     [Google Scholar]
  80. AddieM. BallardP. ButtarD. CrafterC. CurrieG. DaviesB.R. DebreczeniJ. DryH. DudleyP. GreenwoodR. JohnsonP.D. KettleJ.G. LaneC. LamontG. LeachA. LukeR.W.A. MorrisJ. OgilvieD. PageK. PassM. PearsonS. RustonL. Discovery of 4-amino- N -[(1 S )-1-(4-chlorophenyl)-3-hydroxypropyl]-1-(7 H -pyrrolo[2,3- d ]pyrimidin-4-yl)piperidine-4-carboxamide (AZD5363), an orally bioavailable, potent inhibitor of Akt kinases.J. Med. Chem.20135652059207310.1021/jm301762v23394218
     [Google Scholar]
  81. BellacosaA. TestaJ.R.Jr StaalS.P. TsichlisP.N. A retroviral oncogene, akt, encoding a serine-threonine kinase containing an SH2-like region.Science1991254502927427710.1126/science.254.5029.2741833819
     [Google Scholar]
  82. StaalS.P. Molecular cloning of the akt oncogene and its human homologues AKT1 and AKT2: Amplification of AKT1 in a primary human gastric adenocarcinoma.Proc. Natl. Acad. Sci. USA198784145034503710.1073/pnas.84.14.50343037531
     [Google Scholar]
  83. ChengJ.Q. GodwinA.K. BellacosaA. TaguchiT. FrankeT.F. HamiltonT.C. TsichlisP.N. TestaJ.R. AKT2, a putative oncogene encoding a member of a subfamily of protein-serine/threonine kinases, is amplified in human ovarian carcinomas.Proc. Natl. Acad. Sci. USA199289199267927110.1073/pnas.89.19.92671409633
     [Google Scholar]
  84. KonishiH. KurodaS. TanakaM. MatsuzakiH. OnoY. KameyamaK. HagaT. KikkawaU. Molecular cloning and characterization of a new member of the RAC protein kinase family: Association of the pleckstrin homology domain of three types of RAC protein kinase with protein kinase C subspecies and βγ subunits of G proteins.Biochem. Biophys. Res. Commun.1995216252653410.1006/bbrc.1995.26547488143
     [Google Scholar]
  85. UkoN.E. GünerO.F. MatesicD.F. BowenJ.P. Akt pathway inhibitors.Curr. Top. Med. Chem.2020201088390010.2174/156802662066620022410180832091335
     [Google Scholar]
  86. RoyN. BordoloiD. MonishaJ. PadmavathiG. KotokyJ. GollaR. KunnumakkaraA. Specific targeting of Akt kinase isoforms: Taking the precise path for prevention and treatment of cancer.Curr. Drug Targets201718442143510.2174/138945011766616030714523626953242
     [Google Scholar]
  87. MorrowJ.K. Du-CunyL. ChenL. MeuilletE.J. MashE.A. PowisG. ZhangS. Recent development of anticancer therapeutics targeting Akt.Recent Patents Anticancer Drug Discov.20116114615910.2174/15748921179398007921110830
     [Google Scholar]
  88. LerouxA.E. SchulzeJ.O. BiondiR.M. AGC kinases, mechanisms of regulation ‎and innovative drug development.Semin. Cancer Biol.20184811710.1016/j.semcancer.2017.05.01128591657
     [Google Scholar]
  89. HinzN. JückerM. Distinct functions of AKT isoforms in breast cancer: A comprehensive review.Cell Commun. Signal.201917115410.1186/s12964‑019‑0450‑331752925
     [Google Scholar]
  90. HeY. SunM.M. ZhangG.G. YangJ. ChenK.S. XuW.W. LiB. Targeting PI3K/Akt signal transduction for cancer therapy.Signal Transduct. Target. Ther.20216142510.1038/s41392‑021‑00828‑534916492
     [Google Scholar]
  91. YuL. WeiJ. LiuP. Attacking the PI3K/Akt/mTOR signaling pathway for targeted therapeutic treatment in human cancer.Semin. Cancer Biol.202285699410.1016/j.semcancer.2021.06.01934175443
     [Google Scholar]
  92. RascioF. SpadaccinoF. RocchettiM.T. CastellanoG. StalloneG. NettiG.S. RanieriE. The pathogenic role of PI3K/AKT pathway in cancer onset and drug resistance: An updated review.Cancers (Basel)20211316394910.3390/cancers1316394934439105
     [Google Scholar]
  93. BragliaL. ZavattiM. VincetiM. MartelliA.M. MarmiroliS. Deregulated PTEN/PI3K/AKT/mTOR signaling in prostate cancer: Still a potential druggable target?Biochim. Biophys. Acta Mol. Cell Res.20201867911873110.1016/j.bbamcr.2020.11873132360668
     [Google Scholar]
  94. LengyelC.G. AltunaS.C. HabeebB.S. TrapaniD. KhanS.Z. The potential of PI3K/AKT/mTOR signaling as a druggable target for endometrial and ovarian carcinomas.Curr. Drug Targets2020211094696110.2174/138945012066619112012361231752654
     [Google Scholar]
  95. ZhuK. WuY. HeP. FanY. ZhongX. ZhengH. LuoT. PI3K/AKT/mTOR-Targeted therapy for breast cancer.Cells20221116250810.3390/cells1116250836010585
     [Google Scholar]
  96. HashemiM. TaheriazamA. DaneiiP. HassanpourA. kakavandA. RezaeiS. HejaziE.S. AboutalebiM. GholamrezaieH. SaebfarH. SalimimoghadamS. MirzaeiS. EntezariM. SamarghandianS. Targeting PI3K/Akt signaling in prostate cancer therapy.J. Cell Commun. Signal.202317342344310.1007/s12079‑022‑00702‑136367667
     [Google Scholar]
  97. MortazaviM. MoosaviF. MartiniM. GiovannettiE. FiruziO. Prospects of targeting PI3K/AKT/mTOR pathway in pancreatic cancer.Crit. Rev. Oncol. Hematol.202217610374910374910.1016/j.critrevonc.2022.10374935728737
     [Google Scholar]
  98. SanaeiM.J. Baghery Saghchy KhorasaniA. Pourbagheri-SigaroodiA. ShahrokhS. ZaliM.R. BashashD. The PI3K/Akt/mTOR axis in colorectal cancer: Oncogenic alterations, non-coding RNAs, therapeutic opportunities, and the emerging role of nanoparticles.J. Cell. Physiol.202223731720175210.1002/jcp.3065534897682
     [Google Scholar]
  99. HuangJ. ChenL. WuJ. AiD. ZhangJ.Q. ChenT.G. WangL. Targeting the PI3K/AKT/mTOR signaling pathway in the treatment of human diseases: Current status, trends, and solutions.J. Med. Chem.20226524160331606110.1021/acs.jmedchem.2c0107036503229
     [Google Scholar]
  100. LazaroG. KostarasE. VivancoI. Inhibitors in AKTion: ATP-competitive vs. allosteric.Biochem. Soc. Trans.202048393394310.1042/BST2019077732453400
     [Google Scholar]
  101. HiraiH. SootomeH. NakatsuruY. MiyamaK. TaguchiS. TsujiokaK. UenoY. HatchH. MajumderP.K. PanB.S. KotaniH. MK-2206, an allosteric Akt inhibitor, enhances antitumor efficacy by standard chemotherapeutic agents or molecular targeted drugs in vitro and in vivo. Mol. Cancer Ther.2010971956196710.1158/1535‑7163.MCT‑09‑101220571069
     [Google Scholar]
  102. PolitzO. SiegelF. BärfackerL. BömerU. HägebarthA. ScottW.J. MichelsM. InceS. NeuhausR. MeyerK. Fernández-MontalvánA.E. LiuN. von NussbaumF. MumbergD. ZiegelbauerK. BAY 1125976, a selective allosteric AKT1/2 inhibitor, exhibits high efficacy on AKT signaling-dependent tumor growth in mouse models.Int. J. Cancer2017140244945910.1002/ijc.3045727699769
     [Google Scholar]
  103. PolitzO. BaerfackerL. InceS. ScottW.J. NeuhausR. BoemerU. MichelsM. MumbergD. von NussbaumF. ZiegelbauerK. HaegebarthA. Abstract 2050: BAY 1125976, a highly selective and potent allosteric AKT1/2 inhibitor, for the treatment of cancers with aberrations in the PI3K-AKT-mTOR pathway.Cancer Res.2013738_Supplement2050205010.1158/1538‑7445.AM2013‑2050
     [Google Scholar]
  104. YuY. SavageR.E. EathirajS. MeadeJ. WickM.J. HallT. AbbadessaG. SchwartzB. Targeting Akt1-E17K and the PI3K/Akt pathway with an allosteric Akt inhibitor, ARQ 092.PLoS One20151010e014047910.1371/journal.pone.014047926469692
     [Google Scholar]
  105. BlakeJ.F. XuR. BencsikJ.R. XiaoD. KallanN.C. SchlachterS. MitchellI.S. SpencerK.L. BankaA.L. WallaceE.M. GloorS.L. MartinsonM. WoessnerR.D. VigersG.P.A. BrandhuberB.J. LiangJ. SafinaB.S. LiJ. ZhangB. ChabotC. DoS. LeeL. OehJ. SampathD. LeeB.B. LinK. LiedererB.M. SkeltonN.J. Discovery and preclinical pharmacology of a selective ATP-competitive Akt inhibitor (GDC-0068) for the treatment of human tumors.J. Med. Chem.201255188110812710.1021/jm301024w22934575
     [Google Scholar]
  106. CalvoE. BenhadjiK.A. AzaroA. DuranI. ArgilesG. BoniV. OhnmachtU. WallinJ. BumgardnerW.M. Rodon AhnertJ. First-in-human phase I study of LY2780301, an oral P70S6K/AKT inhibitor, in patients with refractory solid tumors.J. Clin. Oncol.20123015_suppl3005300510.1200/jco.2012.30.15_suppl.3005
     [Google Scholar]
  107. AzaroA. RodonJ. CallesA. BrañaI. HidalgoM. Lopez-CasasP.P. MunozM. WestwoodP. MillerJ. MoserB.A. OhnmachtU. BumgardnerW. BenhadjiK.A. CalvoE. A first-in-human phase I trial of LY2780301, a dual p70 S6 kinase and Akt Inhibitor, in patients with advanced or metastatic cancer.Invest. New Drugs201533371071910.1007/s10637‑015‑0241‑725902900
     [Google Scholar]
  108. PalS.K. ReckampK. YuH. FiglinR.A. Akt inhibitors in clinical development for the treatment of cancer.Expert Opin. Investig. Drugs201019111355136610.1517/13543784.2010.52070120846000
     [Google Scholar]
  109. YangJ. CronP. GoodV.M. ThompsonV. HemmingsB.A. BarfordD. Crystal structure of an activated Akt/Protein Kinase B ternary complex with GSK3-peptide and AMP-PNP.Nat. Struct. Biol.200291294094410.1038/nsb87012434148
     [Google Scholar]
  110. Structure of activated form of PKB kinase domain S474D with GSK3 peptide and AMP-PNP.2002Available from: https://www.wwpdb.org/pdb?id=pdb_00001o6k (Accessed on: April 23, 2024).
  111. Crystal structure of an activated Akt/protein kinase B (PKB-PIF chimera) ternary complex with AMP-PNP and GSK3 peptide.2002Available from: https://www.wwpdb.org/pdb?id=pdb_00001o6l (Accessed on: April 23, 2024).
  112. BreitenlechnerC.B. FriebeW.G. BrunetE. WernerG. GraulK. ThomasU. KünkeleK.P. SchäferW. GasselM. BossemeyerD. HuberR. EnghR.A. MasjostB. Design and crystal structures of protein kinase B-selective inhibitors in complex with protein kinase A and mutants.J. Med. Chem.200548116317010.1021/jm049701n15634010
     [Google Scholar]
  113. DaviesT.G. VerdonkM.L. GrahamB. Saalau-BethellS. HamlettC.C.F. McHardyT. CollinsI. GarrettM.D. WorkmanP. WoodheadS.J. JhotiH. BarfordD. A structural comparison of inhibitor binding to PKB, PKA and PKA-PKB chimera.J. Mol. Biol.2007367388289410.1016/j.jmb.2007.01.00417275837
     [Google Scholar]
  114. Structure of PKB-BETA (AKT2) complexed with isoquinoline-5-sulfonic acid (2-(2-(4-chlorobenzyloxy) ethylamino)ethyl)amide.2007Available from: https://www.wwpdb.org/pdb?id=pdb_00002jdo (Accessed on: April 23, 2024).
  115. Structure of PKB-BETA (AKT2) complexed with the inhibitor A-443654.2007Available from: https://www.wwpdb.org/pdb?id=pdb_00002jdr (Accessed on: April 23, 2024).
  116. Structure of PKA-PKB chimera complexed with isoquinoline-5-sulfonic acid (2-(2-(4-chlorobenzyloxy) ethylamino)ethyl)amide.2007Available from: https://www.wwpdb.org/pdb?id=pdb_00002jdt (Accessed on: April 23, 2024).
  117. Structure of PKA-PKB chimera complexed with A-443654.2007Available from: https://www.wwpdb.org/pdb?id=pdb_00002jdv (Accessed on: April 23, 2024).
  118. BlundellT.L. SibandaB.L. MontalvãoR.W. BrewertonS. ChelliahV. WorthC.L. HarmerN.J. DaviesO. BurkeD. Structural biology and bioinformatics in drug design: Opportunities and challenges for target identification and lead discovery.Philos. Trans. R. Soc. Lond. B Biol. Sci.2006361146741342310.1098/rstb.2005.180016524830
     [Google Scholar]
  119. Astex targets CNS with fragment-based approach.Nat. Biopharma Dealmakers2016
     [Google Scholar]
  120. DonaldA. McHardyT. RowlandsM.G. HunterL.J.K. DaviesT.G. BerdiniV. BoyleR.G. AherneG.W. GarrettM.D. CollinsI. Rapid evolution of 6-phenylpurine inhibitors of protein kinase B through structure-based design.J. Med. Chem.200750102289229210.1021/jm070092417451235
     [Google Scholar]
  121. GaßelM. BreitenlechnerC.B. RügerP. JucknischkeU. SchneiderT. HuberR. BossemeyerD. EnghR.A. Mutants of protein kinase A that mimic the ATP-binding site of protein kinase B (AKT).J. Mol. Biol.200332951021103410.1016/S0022‑2836(03)00518‑712798691
     [Google Scholar]
  122. Structure of PKA-PKB chimera complexed with 2-(4-(5-methyl-1H-pyrazol- 4-yl)-phenyl)-ethylamine.2007Available from: https://www.wwpdb.org/pdb?id=pdb_00002uw4 (Accessed on: April 23, 2024).
  123. Structure of PKA-PKB chimera complexed with (R)-2-(4-chloro-phenyl)- 2-(4-1H-pyrazol-4-yl)-phenyl)-ethylamine.2007Available from: https://www.wwpdb.org/pdb?id=pdb_00002uw5 (Accessed on: April 23, 2024).
  124. Structure of PKA-PKB chimera complexed with (S)-2-(4-chloro-phenyl)- 2-(4-1H-pyrazol-4-yl)-phenyl)-ethylamine.2007Available from: https://www.wwpdb.org/pdb?id=pdb_00002uw6 (Accessed on: April 23, 2024).
  125. Structure of PKA-PKB chimera complexed with 4-(4-chloro-phenyl)-4-(4- (1H-pyrazol-4-yl)-phenyl)-piperidine.2007Available from: https://www.wwpdb.org/pdb?id=pdb_00002uw7 (Accessed on: April 23, 2024).
  126. Structure of PKA-PKB chimera complexed with 2-(4-chloro-phenyl)-2- phenyl-ethylamine.2007Available from: https://www.wwpdb.org/pdb?id=pdb_00002uw8 (Accessed on: April 23, 2024).
  127. Structure of PKB-BETA (AKT2) complexed with 4-(4-chloro-phenyl)-4-(4-(1H-pyrazol-4-yl)-phenyl)-piperidine.2007Available from: https://www.wwpdb.org/pdb?id=pdb_00002uw9 (Accessed on: April 23, 2024).
  128. Structure of PKA-PKB chimera complexed with 5-methyl-4-phenyl-1H-pyrazole.2007Available from: https://www.wwpdb.org/pdb?id=pdb_00002uw3 (Accessed on: April 23, 2024).
  129. ZhangH. HeF. GaoG. LuS. WeiQ. HuH. WuZ. FangM. WangX. Approved small-molecule ATPcompetitive kinases drugs containing indole/azaindole/oxindole scaffolds: R&D and binding patterns profiling.Molecules202328394310.3390/molecules2803094336770611
     [Google Scholar]
  130. SaxtyG. WoodheadS.J. BerdiniV. DaviesT.G. VerdonkM.L. WyattP.G. BoyleR.G. BarfordD. DownhamR. GarrettM.D. CarrR.A. Identification of inhibitors of protein kinase B using fragment-based lead discovery.J. Med. Chem.200750102293229610.1021/jm070091b17451234
     [Google Scholar]
  131. McVickerR.U. O’BoyleN.M. Chirality of new drug approvals (2013–2022): Trends and perspectives.J. Med. Chem.20246742305232010.1021/acs.jmedchem.3c0223938344815
     [Google Scholar]
  132. Structure of PKA-PKB chimera complexed with 7-azaindole.2007Available from: https://www.wwpdb.org/pdb?id=pdb_00002uvx (Accessed on: April 23, 2024).
  133. Marcos SantosL. da SilveiraN.J.F. Current fragment- to-lead approaches starting from the 7-azaindole: The pharmacological versatility of a privileged molecular fragment.Curr. Top. Med. Chem.202323222116213010.2174/156802662366623071810054137461366
     [Google Scholar]
  134. da SilveiraN.J.F. de AzevedoW.F. GuedesR.C. SantosL.M. MarcelinoR.C. da Silva AntunesP. EliasT.C. Bioinformatics approach on bioisosterism softwares to be used in drug discovery and development.Curr. Bioinform.2022171193010.2174/1574893616666210525150747
     [Google Scholar]
  135. Structure of PKA-PKB chimera complexed with methyl-(4-(9H-purin-6-yl)- benzyl)-amine.2007Available from: https://www.wwpdb.org/pdb?id=pdb_00002uvy (Accessed on: April 23, 2024).
  136. Structure of PKA-PKB chimera complexed with 6-(4-(4-(4-Chloro-phenyl) -piperidin-4-yl)-phenyl)-9H-purine.2007Available from: https://www.wwpdb.org/pdb?id=pdb_00002uw0 (Accessed on: April 23, 2024).
  137. CaldwellJ.J. DaviesT.G. DonaldA. McHardyT. RowlandsM.G. AherneG.W. HunterL.K. TaylorK. RuddleR. RaynaudF.I. VerdonkM. WorkmanP. GarrettM.D. CollinsI. Identification of 4-(4-aminopiperidin-1-yl)-7H-pyrrolo[2,3-d]pyrimidines as selective inhibitors of protein kinase B through fragment elaboration.J. Med. Chem.20085172147215710.1021/jm701437d18345609
     [Google Scholar]
  138. Structure of PKA-PKB chimera complexed with 4-(4-Chlorobenzyl)-1-(7H-pyrrolo(2,3-d) pyrimidin-4-yl) piperidin-4-ylamine.2008Available from: https://www.wwpdb.org/pdb?id=pdb_00002vo6 (Accessed on: April 23, 2024).
  139. McHardyT. CaldwellJ.J. CheungK.M. HunterL.J. TaylorK. RowlandsM. RuddleR. HenleyA. de Haven BrandonA. ValentiM. DaviesT.G. FazalL. SeaversL. RaynaudF.I. EcclesS.A. AherneG.W. GarrettM.D. CollinsI. Discovery of 4-amino-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamides as selective, orally active inhibitors of protein kinase B (Akt).J. Med. Chem.20105352239224910.1021/jm901788j20151677
     [Google Scholar]
  140. Structure of 4-Amino-N-(4-chlorobenzyl)-1-(7H-pyrrolo(2,3-d)pyrimidin- 4-yl)piperidine-4-carboxamide bound to PKB.2010Available from: https://www.wwpdb.org/pdb?id=pdb_00002x39 (Accessed on: April 23, 2024).
  141. SantosL.M. SantosO.M.M. MendesP.F. RosaI.M.L. SilvaC.C. BonfilioR. de AraujoM.B. BoralliV.B. DoriguettoA.C. MartinsF.T. Identification and proportion of the enantiomers of the antihypertensive drug chlortalidone in its Form II by high quality single-crystal X-ray diffraction data.J. Pharm. Biomed. Anal.201611810110410.1016/j.jpba.2015.10.01526528899
     [Google Scholar]
  142. SantosL.M. LegendreA.O. VillisP.C.M. ViegasC.Jr DoriguettoA.C. (±)-2,2-Dimethyl-5-oxotetrahydrofuran-3-carboxylic acid (terebic acid): A racemic layered structure.Acta Crystallogr. C2012688o294o29710.1107/S010827011202956322850854
     [Google Scholar]
  143. PKB alpha in complex with AZD5363.2013Available from: https://www.wwpdb.org/pdb?id=pdb_00004gv1 (Accessed on: April 23, 2024).
  144. AZD5363.Available from: https://clinicaltrials.gov/search?term=AZD5363 (Accessed on: April 23, 2024).
  145. NierengartenM.B. FDA approves capivasertib with fulvestrant for breast cancer.Cancer2024130683583610.1002/cncr.3523838396318
     [Google Scholar]
  146. FDA approves capivasertib with fulvestrant for breast cancer.2023Available from: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-capivasertib-fulvestrant-breast-cancer (Accessed on: April 23, 2024).
  147. ArnoldM. MorganE. RumgayH. MafraA. SinghD. LaversanneM. VignatJ. GralowJ.R. CardosoF. SieslingS. SoerjomataramI. Current and future burden of breast cancer: Global statistics for 2020 and 2040.Breast202266152310.1016/j.breast.2022.08.01036084384
     [Google Scholar]
  148. Navitoclax.Available from: https://clinicaltrials.gov/search?term=navitoclax (Accessed on: April 23, 2024).
  149. Pelabresib.Available from: https://clinicaltrials.gov/search?term=pelabresib (Accessed on: April 23, 2024).
/content/journals/cmc/10.2174/0109298673331253241004110953
Loading
Medicinal Chemistry behind Capivasertib Discovery: Seventh Magic Bullet of the Fragment-based Drug Design Approved for Oncology
Curr. Med. Chem. 32, 5898 (2025); https://doi.org/10.2174/0109298673331253241004110953
/content/journals/cmc/10.2174/0109298673331253241004110953
/content/journals/cmc/10.2174/0109298673331253241004110953
Loading

Data & Media loading...


  • Article Type:     Review Article
Keyword(s): breast cancer; capivasertib; fragment-based drug design; Medical oncology; medicinal chemistry; protein kinase B (Akt); TruqapTM

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test