Skip to content
2000
Volume 32, Issue 42
  • ISSN: 0929-8673
  • E-ISSN: 1875-533X

Abstract

Branched-chain amino acids (BCAAs) are essential amino acids for humans and play an indispensable role in many physiological and pathological processes. Branched-chain amino acid aminotransferase (BCAT) is a key enzyme that catalyzes the metabolism of BCAAs. BCAT is upregulated in many cancers and implicated in the development and progress of some other diseases, such as metabolic and neurological diseases; and therefore, targeting BCAT might be a potential therapeutic approach for these diseases. There are two isoforms of BCAT, , cytoplasmic BCAT1 (or BCATc) and mitochondrial BCAT2 (or BCATm). The discovery of BCAT inhibitors was initiated by Warner-Lambert, a subsidiary of Pfizer, in 2000, followed by many other pharmaceutical companies, such as GlaxoSmithKline (GSK), Ergon, Icagen, Agios, and Bayer. Strategies of high-throughput screening (HTS), DNA-Encoded library technology (ELT), and fragment-based screening (FBS) have been employed for hit identification, followed by structural optimization. Despite low selectivity, both BCAT1 and BCAT2 selective inhibitors were individually developed, each with a few chemical structural classes. The most advanced BCAT1 inhibitor is BAY-069, discovered by Bayer, which has a potent enzymatic inhibitory activity against BCAT1 and a decent and pharmacokinetic profile but displayed weaker cellular inhibitory activity and almost no anti-proliferative activity. There are no BCAT inhibitors currently under investigation in clinical trials. Further studies are still needed to discover BCAT inhibitors with a more druggable profile for proof of concept. This review focuses on the latest progress of studies on the understanding of the physiology and pathology of BCAT and the discovery and development of BCAT inhibitors. The structure-activity relationship (SAR) and the druggability, and the challenges of BCAT inhibitors are discussed, with the aim of inspiring the discovery and development of BCAT inhibitors in the future.

© 2025 Bentham Science Publishers
Loading

Article metrics loading...

/content/journals/cmc/10.2174/0109298673320136241024054435
2025-01-08
2025-10-30

  • From This Site

    /content/journals/cmc/10.2174/0109298673320136241024054435
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

References

  1. LaymanD.K. The role of leucine in weight loss diets and glucose homeostasis.J. Nutr.20031331261S267S10.1093/jn/133.1.261S12514305
     [Google Scholar]
  2. HolečekM. Branched-chain amino acids in health and disease: Metabolism, alterations in blood plasma, and as supplements.Nutr. Metab.20181513310.1186/s12986‑018‑0271‑129755574
     [Google Scholar]
  3. ZhangS. ZengX. RenM. MaoX. QiaoS. Novel metabolic and physiological functions of branched chain amino acids: A review.J. Anim. Sci. Biotechnol.2017811010.1186/s40104‑016‑0139‑z28127425
     [Google Scholar]
  4. KimballS.R. JeffersonL.S. Signaling pathways and molecular mechanisms through which branched-chain amino acids mediate translational control of protein synthesis.J. Nutr.20061361227S231S10.1093/jn/136.1.227S16365087
     [Google Scholar]
  5. LynchC.J. AdamsS.H. Branched-chain amino acids in metabolic signalling and insulin resistance.Nat. Rev. Endocrinol.2014101272373610.1038/nrendo.2014.17125287287
     [Google Scholar]
  6. YudkoffM. Brain metabolism of branched-chain amino acids.Glia1997211929810.1002/(SICI)1098‑1136(199709)21:1<9 2::AID‑GLIA10>3.0.CO;2‑W9298851
     [Google Scholar]
  7. YeL. WenX. QinJ. ZhangX. WangY. WangZ. ZhouT. DiY. HeW. Metabolism-regulated ferroptosis in cancer progression and therapy.Cell Death Dis.202415319610.1038/s41419‑024‑06584‑y38459004
     [Google Scholar]
  8. DentC.E. RoseG.A. Aminoacid metabolism in cystinuria 1.QJM1951207920521910.1093/oxfordjournals.qjmed.a06661414883297
     [Google Scholar]
  9. SuzukiA. IwataJ. Amino acid metabolism and autophagy in skeletal development and homeostasis.Bone202114611588110.1016/j.bone.2021.11588133578033
     [Google Scholar]
  10. ChenJ. CuiL. LuS. XuS. Amino acid metabolism in tumor biology and therapy.Cell Death Dis.20241514210.1038/s41419‑024‑06435‑w38218942
     [Google Scholar]
  11. LiJ. ChenM. LuL. WangJ. TanL. Branched-chain amino acid transaminase 1 inhibition attenuates childhood asthma in mice by effecting airway remodeling and autophagy.Respir. Physiol. Neurobiol.202230610396110.1016/j.resp.2022.10396135961527
     [Google Scholar]
  12. ToyokawaY. KoonthongkaewJ. TakagiH. An overview of branched-chain amino acid aminotransferases: Functional differences between mitochondrial and cytosolic isozymes in yeast and human.Appl. Microbiol. Biotechnol.202110521-228059807210.1007/s00253‑021‑11612‑434622336
     [Google Scholar]
  13. AnanievaE.A. WilkinsonA.C. Branched-chain amino acid metabolism in cancer.Curr. Opin. Clin. Nutr. Metab. Care2018211647010.1097/MCO.000000000000043029211698
     [Google Scholar]
  14. WangH. WangF. OuyangW. JiangX. WangY. BCAT1 overexpression regulates proliferation and c-Myc/GLUT1 signaling in head and neck squamous cell carcinoma.Oncol. Rep.20214555210.3892/or.2021.800333760210
     [Google Scholar]
  15. HutsonS. Structure and function of branched chain aminotransferases.Prog. Nucleic Acid Res. Mol. Biol.20017017520610.1016/S0079‑6603(01)70017‑711642362
     [Google Scholar]
  16. ZhaoH. ZhangF. SunD. WangX. ZhangX. ZhangJ. YanF. HuangC. XieH. LinC. LiuY. FanM. YanW. ChenY. LianK. LiY. ZhangL. WangS. TaoL. Branched-chain amino acids exacerbate obesity-related hepatic glucose and lipid metabolic disorders via attenuating Akt2 signaling.Diabetes20206961164117710.2337/db19‑092032184272
     [Google Scholar]
  17. WallaceE.R. KoehlL.M. Neurocognitive effects of Moyamoya disease and concomitant epilepsy.Cerebral Circulation - Cognition and Behavior2021210000310.1016/j.cccb.2020.10000336324731
     [Google Scholar]
  18. TönjesM. BarbusS. ParkY.J. WangW. SchlotterM. LindrothA.M. PleierS.V. BaiA.H.C. KarraD. PiroR.M. FelsbergJ. AddingtonA. LemkeD. WeibrechtI. HovestadtV. RolliC.G. CamposB. TurcanS. SturmD. WittH. ChanT.A. MendeH.C. KemkemerR. KönigR. SchmidtK. HullW.E. PfisterS.M. JugoldM. HutsonS.M. PlassC. OkunJ.G. ReifenbergerG. LichterP. RadlwimmerB. BCAT1 promotes cell proliferation through amino acid catabolism in gliomas carrying wild-type IDH1.Nat. Med.201319790190810.1038/nm.321723793099
     [Google Scholar]
  19. WangZ.Q. FaddaouiA. BachvarovaM. PlanteM. GregoireJ. RenaudM.C. SebastianelliA. GuillemetteC. GobeilS. MacdonaldE. VanderhydenB. BachvarovD. BCAT1 expression associates with ovarian cancer progression: Possible implications in altered disease metabolism.Oncotarget2015631315223154310.18632/oncotarget.515926372729
     [Google Scholar]
  20. ZhengY.H. HuW.J. ChenB.C. GrahnT.H.M. ZhaoY.R. BaoH.L. ZhuY.F. ZhangQ.Y. BCAT 1, a key prognostic predictor of hepatocellular carcinoma, promotes cell proliferation and induces chemoresistance to cisplatin.Liver Int.201636121836184710.1111/liv.1317827246112
     [Google Scholar]
  21. ThewesV. SimonR. HlevnjakM. SchlotterM. SchroeterP. SchmidtK. WuY. AnzenederT. WangW. WindischP. KirchgäßnerM. MellingN. KneiselN. BüttnerR. DeuschleU. SinnH.P. SchneeweissA. HeckS. KaulfussS. StumppH.H. OkunJ.G. SauterG. LykkesfeldtA.E. ZapatkaM. RadlwimmerB. LichterP. TönjesM. The branched-chain amino acid transaminase 1 sustains growth of antiestrogen-resistant and ERα-negative breast cancer.Oncogene201736294124413410.1038/onc.2017.3228319069
     [Google Scholar]
  22. MayersJ.R. TorrenceM.E. DanaiL.V. PapagiannakopoulosT. DavidsonS.M. BauerM.R. LauA.N. JiB.W. DixitP.D. HosiosA.M. MuirA. ChinC.R. FreinkmanE. JacksT. WolpinB.M. VitkupD. HeidenV.M.G. Tissue of origin dictates branched-chain amino acid metabolism in mutant Kras -driven cancers.Science201635363041161116510.1126/science.aaf517127609895
     [Google Scholar]
  23. HattoriA. TsunodaM. KonumaT. KobayashiM. NagyT. GlushkaJ. TayyariF. McSkimmingD. KannanN. TojoA. EdisonA.S. ItoT. Cancer progression by reprogrammed BCAA metabolism in myeloid leukaemia.Nature2017545765550050410.1038/nature2231428514443
     [Google Scholar]
  24. RudinC.M. BrambillaE. FinnF.C. SageJ. Small-cell lung cancer.Nat. Rev. Dis. Primers202171310.1038/s41572‑020‑00235‑033446664
     [Google Scholar]
  25. ZhuW. ShaoY. PengY. MicroRNA-218 inhibits tumor growth and increases chemosensitivity to CDDP treatment by targeting BCAT1 in prostate cancer.Mol. Carcinog.20175661570157710.1002/mc.2261228052414
     [Google Scholar]
  26. SheP. ZhouY. ZhangZ. GriffinK. GowdaK. LynchC.J. Disruption of BCAA metabolism in mice impairs exercise metabolism and endurance.J. Appl. Physiol.2010108494194910.1152/japplphysiol.01248.200920133434
     [Google Scholar]
  27. NewgardC.B. AnJ. BainJ.R. MuehlbauerM.J. StevensR.D. LienL.F. HaqqA.M. ShahS.H. ArlottoM. SlentzC.A. RochonJ. GallupD. IlkayevaO. WennerB.R. YancyW.S.Jr EisensonH. MusanteG. SurwitR.S. MillingtonD.S. ButlerM.D. SvetkeyL.P. A branched-chain amino acid-related metabolic signature that differentiates obese and lean humans and contributes to insulin resistance.Cell Metab.20099431132610.1016/j.cmet.2009.02.00219356713
     [Google Scholar]
  28. LoombaR. AbrahamM. UnalpA. WilsonL. LavineJ. DooE. BassN.M. Association between diabetes, family history of diabetes, and risk of nonalcoholic steatohepatitis and fibrosis.Hepatology201256394395110.1002/hep.2577222505194
     [Google Scholar]
  29. KusminskiC.M. ShettyS. OrciL. UngerR.H. SchererP.E. Diabetes and apoptosis: Lipotoxicity.Apoptosis200914121484149510.1007/s10495‑009‑0352‑819421860
     [Google Scholar]
  30. LoombaR. SanyalA.J. The global NAFLD epidemic.Nat. Rev. Gastroenterol. Hepatol.2013101168669010.1038/nrgastro.2013.17124042449
     [Google Scholar]
  31. GrecoD. KotronenA. WesterbackaJ. PuigO. ArkkilaP. KiviluotoT. LaitinenS. KolakM. FisherR.M. HamstenA. AuvinenP. JärvinenY.H. Gene expression in human NAFLD.Am. J. Physiol. Gastrointest. Liver Physiol.20082945G1281G128710.1152/ajpgi.00074.200818388185
     [Google Scholar]
  32. ChenC. NaveedH. ChenK. Research progress on branched-chain amino acid aminotransferases.Front. Genet.202314123366910.3389/fgene.2023.123366938028625
     [Google Scholar]
  33. HuangW. HaoZ. MaoF. GuoD. Small molecule inhibitors in adult high-grade glioma: From the past to the future.Front. Oncol.20221291187610.3389/fonc.2022.91187635785151
     [Google Scholar]
  34. HolečekM. Why are branched-chain amino acids increased in starvation and diabetes?Nutrients20201210308710.3390/nu1210308733050579
     [Google Scholar]
  35. SperringerJ.E. AddingtonA. HutsonS.M. Branched-chain amino acids and brain metabolism.Neurochem. Res.20174261697170910.1007/s11064‑017‑2261‑528417264
     [Google Scholar]
  36. YudkoffM. Interactions in the metabolism of glutamate and the branched-chain amino acids and ketoacids in the CNS.Neurochem. Res.2017421101810.1007/s11064‑016‑2057‑z27696119
     [Google Scholar]
  37. HullJ. PatelV.B. HutsonS.M. ConwayM.E. New insights into the role of the branched-chain aminotransferase proteins in the human brain.J. Neurosci. Res.201593798799810.1002/jnr.2355825639459
     [Google Scholar]
  38. AdamsS.H. Emerging perspectives on essential amino acid metabolism in obesity and the insulin-resistant state.Adv. Nutr.20112644545610.3945/an.111.00073722332087
     [Google Scholar]
  39. BezsudnovaE.Y. StekhanovaT.N. SuplatovD.A. MardanovA.V. RavinN.V. PopovV.O. Experimental and computational studies on the unusual substrate specificity of branched-chain amino acid aminotransferase from Thermoproteus uzoniensis.Arch. Biochem. Biophys.2016607273610.1016/j.abb.2016.08.00927523731
     [Google Scholar]
  40. HullJ. PatelV. HindyE.M. LeeC. OdeleyeE. HezwaniM. LoveS. KehoeP. ChalmersK. ConwayM. Regional increase in the expression of the BCAT proteins in Alzheimer’s disease brain: Implications in glutamate toxicity.J. Alzheimers Dis.201545389190510.3233/JAD‑14297025633671
     [Google Scholar]
  41. ConwayM.E. Emerging moonlighting functions of the branched-chain aminotransferase proteins.Antioxid. Redox Signal.202134131048106710.1089/ars.2020.811832635740
     [Google Scholar]
  42. SuryawanA. HawesJ.W. HarrisR.A. ShimomuraY. JenkinsA.E. HutsonS.M. A molecular model of human branched-chain amino acid metabolism.Am. J. Clin. Nutr.1998681728110.1093/ajcn/68.1.729665099
     [Google Scholar]
  43. YudkoffM. DaikhinY. NissimI. HorynO. LuhovyyB. LazarowA. NissimI. NissimI. Brain amino acid requirements and toxicity: The example of leucine.J. Nutr.200513561531S1538S10.1093/jn/135.6.1531S15930465
     [Google Scholar]
  44. AnanievaE.A. PowellJ.D. HutsonS.M. Leucine metabolism in T cell activation: MTOR signaling and beyond.Adv. Nutr.201674798S805S10.3945/an.115.01122127422517
     [Google Scholar]
  45. IchiharaA. KoyamaE. Transaminase of branched chain amino acids. I. Branched chain amino acids-α-ketoglutarate transaminase.J. Biochem.196659216016910.1093/oxfordjournals.jbchem.a1282775943594
     [Google Scholar]
  46. WetzelT.J. ErfanS.C. AnanievaE.A. The emerging role of the branched chain aminotransferases, BCATc and BCATm, for anti-tumor T-cell immunity.Immunometabolism202351e0001410.1097/IN9.000000000000001436644500
     [Google Scholar]
  47. SivanandS. HeidenV.M.G. Emerging roles for branched-chain amino acid metabolism in cancer.Cancer Cell202037214715610.1016/j.ccell.2019.12.01132049045
     [Google Scholar]
  48. DimouA. TsimihodimosV. BairaktariE. The critical role of the branched chain amino acids (BCAAs) catabolism-regulating enzymes, branched-chain aminotransferase (BCAT) and branched-chain α-keto acid dehydrogenase (BCKD), in human pathophysiology.Int. J. Mol. Sci.2022237402210.3390/ijms2307402235409380
     [Google Scholar]
  49. CostanzoM. VanderSluisB. KochE.N. BaryshnikovaA. PonsC. TanG. WangW. UsajM. HanchardJ. LeeS.D. PelechanoV. StylesE.B. BillmannM. LeeuwenV.J. DykV.N. LinZ.Y. KuzminE. NelsonJ. PiotrowskiJ.S. SrikumarT. BahrS. ChenY. DeshpandeR. KuratC.F. LiS.C. LiZ. UsajM.M. OkadaH. PascoeN. San LuisB.J. SharifpoorS. ShuteriqiE. SimpkinsS.W. SniderJ. SureshH.G. TanY. ZhuH. DogninM.N. JanjicV. PrzuljN. TroyanskayaO.G. StagljarI. XiaT. OhyaY. GingrasA.C. RaughtB. BoutrosM. SteinmetzL.M. MooreC.L. RosebrockA.P. CaudyA.A. MyersC.L. AndrewsB. BooneC. A global genetic interaction network maps a wiring diagram of cellular function.Science20163536306aaf142010.1126/science.aaf142027708008
     [Google Scholar]
  50. YuA.Q. JuwonoP.N.K. FooJ.L. LeongS.S.J. ChangM.W. Metabolic engineering of Saccharomyces cerevisiae for the overproduction of short branched-chain fatty acids.Metab. Eng.201634364310.1016/j.ymben.2015.12.00526721212
     [Google Scholar]
  51. CamposR.M. MoscatJ. MecoD.M. Metabolism shapes the tumor microenvironment.Curr. Opin. Cell Biol.201748475310.1016/j.ceb.2017.05.00628605656
     [Google Scholar]
  52. DeBerardinisR.J. ChandelN.S. Fundamentals of cancer metabolism.Sci. Adv.201625e160020010.1126/sciadv.160020027386546
     [Google Scholar]
  53. XuW. YangH. LiuY. YangY. WangP. KimS.H. ItoS. YangC. WangP. XiaoM.T. LiuL. JiangW. LiuJ. ZhangJ. WangB. FryeS. ZhangY. XuY. LeiQ. GuanK.L. ZhaoS. XiongY. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of α-ketoglutarate-dependent dioxygenases.Cancer Cell2011191173010.1016/j.ccr.2010.12.01421251613
     [Google Scholar]
  54. DangL. WhiteD.W. GrossS. BennettB.D. BittingerM.A. DriggersE.M. FantinV.R. JangH.G. JinS. KeenanM.C. MarksK.M. PrinsR.M. WardP.S. YenK.E. LiauL.M. RabinowitzJ.D. CantleyL.C. ThompsonC.B. HeidenV.M.G. SuS.M. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate.Nature2009462727473974410.1038/nature0861719935646
     [Google Scholar]
  55. DeyP. BaddourJ. MullerF. WuC.C. WangH. LiaoW.T. LanZ. ChenA. GutschnerT. KangY. FlemingJ. SataniN. ZhaoD. AchrejaA. YangL. LeeJ. ChangE. GenoveseG. VialeA. YingH. DraettaG. MaitraA. WangY.A. NagrathD. DePinhoR.A. Genomic deletion of malic enzyme 2 confers collateral lethality in pancreatic cancer.Nature2017542763911912310.1038/nature2105228099419
     [Google Scholar]
  56. HuL.Y. BoxerP.A. KestenS.R. LeiH.J. WustrowD.J. MorelandD.W. ZhangL. AhnK. RyderT.R. LiuX. RubinJ.R. FahnoeK. CarrollR.T. DuttaS. FahnoeD.C. ProbertA.W. RoofR.L. RaffertyM.F. KostlanC.R. ScholtenJ.D. HoodM. RenX.D. SchielkeG.P. SuT.Z. TaylorC.P. MistryA. McConnellP. HasemannC. OhrenJ. The design and synthesis of human branched-chain amino acid aminotransferase inhibitors for treatment of neurodegenerative diseases.Bioorg. Med. Chem. Lett.20061692337234010.1016/j.bmcl.2005.07.05816143519
     [Google Scholar]
  57. RaffelS. FalconeM. KneiselN. HanssonJ. WangW. LutzC. BullingerL. PoschetG. NonnenmacherY. BarnertA. BahrC. ZeisbergerP. PrzybyllaA. SohnM. TönjesM. ErezA. AdlerL. JensenP. SchollC. FröhlingS. CocciardiS. WuchterP. ThiedeC. FlörckenA. WestermannJ. EhningerG. LichterP. HillerK. HellR. HerrmannC. HoA.D. KrijgsveldJ. RadlwimmerB. TrumppA. BCAT1 restricts αKG levels in AML stem cells leading to IDHmut-like DNA hypermethylation.Nature2017551768038438810.1038/nature2429429144447
     [Google Scholar]
  58. RaffelS. FalconeM. KneiselN. HanssonJ. WangW. LutzC. BullingerL. PoschetG. NonnenmacherY. BarnertA. BahrC. ZeisbergerP. PrzybyllaA. SohnM. TönjesM. ErezA. AdlerL. JensenP. SchollC. FröhlingS. CocciardiS. WuchterP. ThiedeC. FlörckenA. WestermannJ. EhningerG. LichterP. HillerK. HellR. HerrmannC. HoA.D. KrijgsveldJ. RadlwimmerB. TrumppA. Author correction: BCAT1 restricts αKG levels in AML stem cells leading to IDHmut-like DNA hypermethylation.Nature20185607718E2810.1038/s41586‑018‑0403‑930069041
     [Google Scholar]
  59. ChattopadhyayI. WangJ. QinM. GaoL. HoltzR. VessellaR.L. LeachR.W. GelmanI.H. Src promotes castration-recurrent prostate cancer through androgen receptor-dependent canonical and non-canonical transcriptional signatures.Oncotarget201786103241034710.18632/oncotarget.1440128055971
     [Google Scholar]
  60. ShafeiM.A. FlembanA. DalyC. KendrickP. WhiteP. DeanS. QualtroughD. ConwayM.E. Differential expression of the BCAT isoforms between breast cancer subtypes.Breast Cancer202128359260710.1007/s12282‑020‑01197‑733367952
     [Google Scholar]
  61. LiJ.T. YinM. WangD. WangJ. LeiM.Z. ZhangY. LiuY. ZhangL. ZouS.W. HuL.P. ZhangZ.G. WangY.P. WenW.Y. LuH.J. ChenZ.J. SuD. LeiQ.Y. BCAT2-mediated BCAA catabolism is critical for development of pancreatic ductal adenocarcinoma.Nat. Cell Biol.202022216717410.1038/s41556‑019‑0455‑632029896
     [Google Scholar]
  62. HalbrookC.J. LyssiotisC.A. Employing metabolism to improve the diagnosis and treatment of pancreatic cancer.Cancer Cell201731151910.1016/j.ccell.2016.12.00628073003
     [Google Scholar]
  63. WangY.T. ZhangJ. RenS.X. SunD. HuangH.Y. WangH. JinY.J. LiF.M. ZhengC. YangL. DengL. JiangZ.L. JiangT. HanX.K. HouS.D. GuoC.C. LiF. GaoD. QinJ. GaoD.M. ChenL.N. LinS.H. WongK.K. LiC. HuL. ZhouC.C. JiH.B. Branched-chain amino acid metabolic reprogramming orchestrates drug resistance to EGFR tyrosine kinase inhibitors.Cell Rep.2019282512525.E610.1016/j.celrep.2019.06.026
     [Google Scholar]
  64. SilvaL.S. PoschetG. NonnenmacherY. BeckerH.M. SapcariuS. GaupelA.C. SchlotterM. WuY. KneiselN. SeiffertM. HellR. HillerK. LichterP. RadlwimmerB. Branched-chain ketoacids secreted by glioblastoma cells via MCT 1 modulate macrophage phenotype.EMBO Rep.201718122172218510.15252/embr.20174415429066459
     [Google Scholar]
  65. ChenJ. BarrettL. LinZ. KendrickS. MuS. DaiL. QinZ. Identification of natural compounds tubercidin and lycorine HCl against small-cell lung cancer and BCAT1 as a therapeutic target.J. Cell. Mol. Med.20222692557256510.1111/jcmm.1724635318805
     [Google Scholar]
  66. TsengY.H. YangR.C. ChiouS.S. ShiehT.M. ShihY.H. LinP.C. Curcumin induces apoptosis by inhibiting BCAT1 expression and mTOR signaling in cytarabine-resistant myeloid leukemia cells.Mol. Med. Rep.202124256510.3892/mmr.2021.1220434109436
     [Google Scholar]
  67. HermanM.A. SheP. PeroniO.D. LynchC.J. KahnB.B. Adipose tissue branched chain amino acid (BCAA) metabolism modulates circulating BCAA levels.J. Biol. Chem.201028515113481135610.1074/jbc.M109.07518420093359
     [Google Scholar]
  68. PietiläinenK.H. NaukkarinenJ. RissanenA. SaharinenJ. EllonenP. KeränenH. SuomalainenA. GötzA. SuorttiT. JärvinenY.H. OrešičM. KaprioJ. PeltonenL. Global transcript profiles of fat in monozygotic twins discordant for BMI: Pathways behind acquired obesity.PLoS Med.200853e5110.1371/journal.pmed.005005118336063
     [Google Scholar]
  69. VanweertF. LigtD.M. HoeksJ. HesselinkM.K.C. SchrauwenP. PhielixE. Elevated plasma branched-chain amino acid levels correlate with type 2 diabetes-related metabolic disturbances.J. Clin. Endocrinol. Metab.20211064e1827e183610.1210/clinem/dgaa75133079174
     [Google Scholar]
  70. SheP. ReidT.M. BronsonS.K. VaryT.C. HajnalA. LynchC.J. HutsonS.M. Disruption of BCATm in mice leads to increased energy expenditure associated with the activation of a futile protein turnover cycle.Cell Metab.20076318119410.1016/j.cmet.2007.08.00317767905
     [Google Scholar]
  71. BorthwickJ.A. AncellinN. BertrandS.M. BinghamR.P. CarterP.S. ChungC. ChurcherI. DodicN. FournierC. FrancisP.L. HobbsA. JamiesonC. PickettS.D. SmithS.E. SomersD.O.N. SpitzfadenC. SucklingC.J. YoungR.J. Structurally diverse mitochondrial branched chain aminotransferase (BCATm) leads with varying binding modes identified by fragment screening.J. Med. Chem.20165962452246710.1021/acs.jmedchem.5b0160726938474
     [Google Scholar]
  72. LuZ. SunG.F. PanX.A. QuX.H. YangP. ChenZ.P. HanX.J. WangT. BCATc inhibitor 2 ameliorated mitochondrial dysfunction and apoptosis in oleic acid-induced non-alcoholic fatty liver disease model.Front. Pharmacol.202213102555110.3389/fphar.2022.102555136386234
     [Google Scholar]
  73. LiethE. LaNoueK.F. BerkichD.A. XuB. RatzM. TaylorC. HutsonS.M. Nitrogen shuttling between neurons and glial cells during glutamate synthesis.J. Neurochem.20017661712172310.1046/j.1471‑4159.2001.00156.x11259489
     [Google Scholar]
  74. KholodilovN.G. NeystatM. OoT.F. HutsonS.M. BurkeR.E. Upregulation of cytosolic branched chain aminotransferase in substantia nigra following developmental striatal target injury.Brain Res. Mol. Brain Res.200075228128610.1016/S0169‑328X(99)00318‑610686349
     [Google Scholar]
  75. JouvetP. RustinP. TaylorD.L. PocockJ.M. MueserF.U. MazarakisN.D. SarrafC. JoashiU. KozmaM. GreenwoodK. EdwardsA.D. MehmetH. Branched chain amino acids induce apoptosis in neural cells without mitochondrial membrane depolarization or cytochrome c release: Implications for neurological impairment associated with maple syrup urine disease.Mol. Biol. Cell20001151919193210.1091/mbc.11.5.191910793161
     [Google Scholar]
  76. HarrisM. HindyE.M. MoraesU.M. HuddF. ShafeiM. DongM. HezwaniM. ClarkP. HouseM. ForshawT. KehoeP. ConwayM.E. BCAT-induced autophagy regulates Aβ load through an interdependence of redox state and PKC phosphorylation-implications in Alzheimer’s disease.Free Radic. Biol. Med.202015275576610.1016/j.freeradbiomed.2020.01.01931982508
     [Google Scholar]
  77. MorD.E. SohrabiS. KaletskyR. KeyesW. TarticiA. KaliaV. MillerG.W. MurphyC.T. Metformin rescues Parkinson’s disease phenotypes caused by hyperactive mitochondria.Proc. Natl. Acad. Sci.202011742264382644710.1073/pnas.200983811733024014
     [Google Scholar]
  78. CaballeroJ. JaqueV.A. FernándezM. CollD. Docking and quantitative structure–activity relationship studies for sulfonyl hydrazides as inhibitors of cytosolic human branched-chain amino acid aminotransferase.Mol. Divers.200913449350010.1007/s11030‑009‑9140‑119350404
     [Google Scholar]
  79. BoraK.M. HuL-Y. KestenS.R. LeiH. MorelandD.W. RaffertyM.F. RyderT.R. ScholtenJ.D. WustrowD.J. Branched chain amino acid-dependent aminotransferase inhibitors and their use in the treatment of neurodegenerative diseases.Patent: WO, 02/24672, A2, 2003
  80. HuL.Y. KestenS.R. LeiH. RyderT.R. WustrowD.J. Branched chain amino acid-dependent aminotransferase inhibitors and their use in the treatment of neurodegenerative diseases.Patent: WO, 03/045902, A1, 2003
  81. KukkarA. BaliA. SinghN. JaggiA.S. Implications and mechanism of action of gabapentin in neuropathic pain.Arch. Pharm. Res.201336323725110.1007/s12272‑013‑0057‑y23435945
     [Google Scholar]
  82. ChenY. WuQ. JinZ. QinY. MengF. ZhaoG. Review of voltage-gated calcium channel α2δ subunit ligands for the treatment of chronic neuropathic pain and insight into structure-activity relationship (SAR) by pharmacophore modeling.Curr. Med. Chem.202229305097511210.2174/092986732966622040709372735392779
     [Google Scholar]
  83. HutsonS.M. BerkichD. DrownP. XuB. AschnerM. LaNoueK.F. Role of branched-chain aminotransferase isoenzymes and gabapentin in neurotransmitter metabolism.J. Neurochem.199871286387410.1046/j.1471‑4159.1998.71020863.x9681479
     [Google Scholar]
  84. GotoM. MiyaharaI. HirotsuK. ConwayM. YennawarN. IslamM.M. HutsonS.M. Structural determinants for branched-chain aminotransferase isozyme-specific inhibition by the anticonvulsant drug gabapentin.J. Biol. Chem.200528044372463725610.1074/jbc.M50648620016141215
     [Google Scholar]
  85. RadlwimmerB. BarbusS. TönjesM. TödtG. LichterP. ReifenbergerG. Methods for the diagnosis and prognosis of a tumor using BCAT1 protein.Patent: WO, 2011/141153, A1, 2011
  86. RadlwimmerB. TönjesM. BarbusS. LichterP. Inhibitors of branched-chain aminotransferase 1 (BCAT1) for the treatment of brain tumors.Patent: WO, 2012/100957, A1, 2012
  87. GrankvistN. LagerborgK.A. JainM. NilssonR. Gabapentin can suppress cell proliferation independent of the cytosolic branched-chain amino acid transferase 1 (BCAT1).Biochem.201857496762676610.1021/acs.biochem.8b0103130427175
     [Google Scholar]
  88. BryansJ.S. HuL.Y. HutsonS.M. LaNoueK.F. LiethE. RaffertyM.F. RyderT.R. Branched chain amino acid-dependent aminotransferase inhibitors and their use in the treatment of diabetic retinopathy.Patent: WO, 01/42191, A1, 2001
  89. PapathanassiuA.E. Methods of treatment using a BCAT1 inhibitor.Patent: WO, 2012/173987, A22012
  90. PapathanassiuA.E. Compositions and methods of treatment using a BCAT1 inhibitor.Patent: US, 2016/0368862, A1,2016
  91. GüntherJ. HilligR.C. ZimmermannK. KaulfussS. LemosC. NguyenD. RehwinkelH. HabgoodM. LechnerC. NeuhausR. GanzerU. DrewesM. ChaiJ. BouchéL. BAY-069, a novel (trifluoromethyl) pyrimidinedione-based BCAT1/2 inhibitor and chemical probe.J. Med. Chem.20226521143661439010.1021/acs.jmedchem.2c0044136261130
     [Google Scholar]
  92. BoucheL.A. KaulfussS. ZimmermannK. RehwinkelH. NeuhausR. HilligR. NguyenD. GüntherJ. LemosF.A.D.C.A. Pyrimidinedione derivatives.Patent: WO, 2021/063821, A1, 2021
  93. HaysS.J. HuL.-Y. LeiH. ScholtenJ.D. WustrowD.J. Branched chain amino acid-dependent aminotransferase inhibitors and their use in the treatment of neurodegenerative diseases.Patent: WO, 03/045384, A1, 2003
  94. DengH. ZhouJ. SundersinghF. MesserJ.A. SomersD.O. AjakaneM. MuendelA.C.C. BeljeanA. BelyanskayaS.L. BinghamR. BlazenskyE. BoullayA.B. BoursierE. ChaiJ. CarterP. ChungC.W. DauganA. DingY. HerryK. HobbsC. HumphriesE. KollmannC. NguyenV.L. NicodemeE. SmithS.E. DodicN. AncellinN. Discovery and optimization of potent, selective, and in vivo efficacious 2-aryl benzimidazole BCATm inhibitors.ACS Med. Chem. Lett.20167437938410.1021/acsmedchemlett.5b0038927096045
     [Google Scholar]
  95. AugustP.R. KenneyM. MaugerJ. DrewM. KongW. BCAT modulation.Patent: WO, 2021/007350, A1, 2021
  96. BarberisC. LiuP. BCAT2 inhibitors.Patent: WO, 2023/086539, A2, 2023
  97. DengH. ZhouJ. SundersinghF.S. SummerfieldJ. SomersD. MesserJ.A. SatzA.L. AncellinN. MuendelA.C.C. BedardS.K.L. BeljeanA. BelyanskayaS.L. BinghamR. SmithS.E. BoursierE. CarterP. CentrellaP.A. ClarkM.A. ChungC.W. DavieC.P. DeloreyJ.L. DingY. FranklinG.J. GradyL.C. HerryK. HobbsC. KollmannC.S. MorganB.A. KaushanskyP.L.J. ZhouQ. Discovery, SAR, and X-ray binding mode study of BCATm inhibitors from a novel DNA-encoded library.ACS Med. Chem. Lett.20156891992410.1021/acsmedchemlett.5b0017926288694
     [Google Scholar]
  98. BertrandS.M. AncellinN. BeaufilsB. BinghamR.P. BorthwickJ.A. BoullayA.B. BoursierE. CarterP.S. ChungC. ChurcherI. DodicN. FouchetM.H. FournierC. FrancisP.L. GummerL.A. HerryK. HobbsA. HobbsC.I. HomesP. JamiesonC. NicodemeE. PickettS.D. ReidI.H. SimpsonG.L. SloanL.A. SmithS.E. SomersD.O.N. SpitzfadenC. SucklingC.J. ValkoK. WashioY. YoungR.J. The discovery of in vivo active mitochondrial branched-chain aminotransferase (BCATm) inhibitors by hybridizing fragment and HTS hits.J. Med. Chem.201558187140716310.1021/acs.jmedchem.5b0031326090771
     [Google Scholar]
  99. LeiQ. MaQ. YinM. Application of BCAT2 inhibitor in preparation of medicine for preventing and/or treating BCAT2-mediated related metabolic diseases.Patent: CN, 114073697,2022
  100. QianL. LiN. LuX.C. XuM. LiuY. LiK. ZhangY. HuK. QiY.T. YaoJ. WuY.L. WenW. HuangS. ChenZ.J. YinM. LeiQ.Y. Enhanced BCAT1 activity and BCAA metabolism promotes RhoC activity in cancer progression.Nat. Metab.2023571159117310.1038/s42255‑023‑00818‑737337119
     [Google Scholar]
  101. RayP.K. SalahuddinS. MazumderA. KumarR. AhsanM.J. YarS.M. Salahuddin MazumderA. KumarR. AhsanM.J. YarM.S. Synthesis, anticonvulsant, and molecular docking studies of (3,5-disubstituted-4,5-dihydro-1H-pyrazol-1-yl) (4-chlorophenyl) methanone derivatives.Indian J. Pharm. Edu. Res.202357120220910.5530/001954641727
     [Google Scholar]
  102. FuF. LaiQ. HuJ. ZhangL. ZhuX. KouJ. YuB. LiF. Ruscogenin alleviates myocardial ischemia-induced ferroptosis through the activation of BCAT1/BCAT2.Antioxidants202211358310.3390/antiox1103058335326233
     [Google Scholar]
/content/journals/cmc/10.2174/0109298673320136241024054435
Loading
A Review on Branched-Chain Amino Acid Aminotransferase (BCAT) Inhibitors: Current Status, Challenges and Perspectives
Curr. Med. Chem. 32, 9533 (2025); https://doi.org/10.2174/0109298673320136241024054435
/content/journals/cmc/10.2174/0109298673320136241024054435
/content/journals/cmc/10.2174/0109298673320136241024054435
Loading

Data & Media loading...


  • Article Type:     Review Article
Keyword(s): BAY-069; Branched-chain amino acid (BCAA); branched-chain amino acid aminotransferase (BCAT); DNA-encoded library; structure-activity relationship (SAR); tumor

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