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2000
Volume 25, Issue 7
  • ISSN: 1568-0096
  • E-ISSN: 1873-5576

Abstract

Cyclin-dependent Kinase 12 (CDK12) is a Cyclin-dependent Kinase (CDK) that plays a crucial role in various biological processes, including transcription, translation, mRNA splicing, cell cycle regulation, and DNA damage repair. Dysregulation of CDK12 has been implicated in tumorigenesis, and genetic alterations affecting CDK12 have been identified in multiple cancer types, including breast cancer, ovarian cancer, gastric cancer, and prostate cancer. Numerous studies have demonstrated that suppression of CDK12 expression effectively inhibits tumor growth and proliferation, underscoring its significance as a cancer biomarker and a potential therapeutic target in cancer treatment. A thorough comprehension of CDK12 is expected to significantly enhance the advancement of novel approaches for the treatment and prevention of cancer. In recent times, endeavors have been undertaken to formulate targeted inhibitors for CDK12, such as PROTAC and molecular gel degraders. Concurrently, investigations have been conducted on the combined utilization of CDK12 small molecule inhibitors and immunotherapy as a potential strategy. This paper examines the diverse functions of CDK12 in the modulation of gene expression and its implications in human tumors. Specifically, it explores the recently uncovered roles of CDK12 kinases in various cellular processes, emphasizing the potential of CDK12 as a viable therapeutic target for the management of human tumors. Furthermore, this review provides an up-to-date account of the advancements made in utilizing CDK12 in tumor therapy.

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References

  1. ŁukasikP. ZałuskiM. GutowskaI. Cyclin-Dependent Kinases (CDK) and their role in diseases development–review.Int. J. Mol. Sci.2021226293510.3390/ijms2206293533805800
     [Google Scholar]
  2. ChouJ. QuigleyD.A. RobinsonT.M. FengF.Y. AshworthA. Transcription-associated cyclin-dependent kinases as targets and biomarkers for cancer therapy.Cancer Discov.202010335137010.1158/2159‑8290.CD‑19‑052832071145
     [Google Scholar]
  3. MounikaP. GurupadayyaB. KumarH.Y. NamithaB. An overview of CDK enzyme inhibitors in cancer therapy.Curr. Cancer Drug Targets202323860361910.2174/156800962366623032014471336959160
     [Google Scholar]
  4. BaiN. XiaF. WangW. LeiY. BoJ. LiX. CDK12 promotes papillary thyroid cancer progression through regulating the c-myc/β-catenin pathway.J. Cancer202011154308431510.7150/jca.4284932489449
     [Google Scholar]
  5. PengF. YangC. KongY. HuangX. ChenY. ZhouY. XieX. LiuP. CDK12 promotes breast cancer progression and maintains stemness by activating c-myc/β -catenin signaling.Curr. Cancer Drug Targets202020215616510.2174/156800961966619111811322031744448
     [Google Scholar]
  6. ChoiH.J. JinS. ChoH. WonH.Y. AnH.W. JeongG.Y. ParkY.U. KimH.Y. ParkM.K. SonT. MinK.W. JangK.S. OhY.H. LeeJ.Y. KongG. CDK 12 drives breast tumor initiation and trastuzumab resistance via WNT and IRS 1‐ErbB‐ PI 3K signaling.EMBO Rep.20192010e4805810.15252/embr.20194805831468695
     [Google Scholar]
  7. HenryK.L. KellnerD. BajramiB. AndersonJ.E. BeynaM. BhisettiG. CameronT. CapacciA.G. Bertolotti-CiarletA. FengJ. GaoB. HopkinsB. JenkinsT. LiK. May-DrackaT. MuruganP. WeiR. ZengW. AllaireN. BucklerA. LohC. JuhaszP. LucasB. EnnisK.A. VollmanE. Cahir-McFarlandE. HettE.C. OlsM.L. CDK12-mediated transcriptional regulation of noncanonical NF-κB components is essential for signaling.Sci. Signal.201811541eaam821610.1126/scisignal.aam821630065029
     [Google Scholar]
  8. NaidooK. WaiP.T. MaguireS.L. DaleyF. HaiderS. KriplaniD. CampbellJ. MirzaH. GrigoriadisA. TuttA. MoseleyP.M. Abdel-FatahT.M.A. ChanS.Y.T. MadhusudanS. RhakaE.A. EllisI.O. LordC.J. YuanY. GreenA.R. NatrajanR. Evaluation of CDK12 protein expression as a potential novel biomarker for dna damage response–targeted therapies in breast cancer.Mol. Cancer Ther.201817130631510.1158/1535‑7163.MCT‑17‑076029133620
     [Google Scholar]
  9. LiuH. ShinS.H. ChenH. LiuT. LiZ. HuY. LiuF. ZhangC. KimD.J. LiuK. DongZ. CDK12 and PAK2 as novel therapeutic targets for human gastric cancer.Theranostics202010146201621510.7150/thno.4613732483448
     [Google Scholar]
  10. LiangS. HuL. WuZ. ChenZ. LiuS. XuX. QianA. CDK12: A potent target and biomarker for human cancer therapy.Cells202096148310.3390/cells906148332570740
     [Google Scholar]
  11. GreenleafA.L. Human CDK12 and CDK13, multi-tasking CTD kinases for the new millenium.Transcription20191029111010.1080/21541264.2018.153521130319007
     [Google Scholar]
  12. WangL. YangZ. LiG. LiuY. AiC. RaoY. Discovery of small molecule degraders for modulating cell cycle.Front. Med.202317582385410.1007/s11684‑023‑1027‑537935945
     [Google Scholar]
  13. EmadiF. TeoT. RahamanM.H. WangS. CDK12: a potential therapeutic target in cancer.Drug Discov. Today202025122257226710.1016/j.drudis.2020.09.03533038524
     [Google Scholar]
  14. LuX. SmaillJ.B. PattersonA.V. DingK. Discovery of cysteine-targeting covalent protein kinase inhibitors.J. Med. Chem.2022651588310.1021/acs.jmedchem.1c0171934962782
     [Google Scholar]
  15. ChenH.H. WangY.C. FannM.J. Identification and characterization of the CDK12/cyclin L1 complex involved in alternative splicing regulation.Mol. Cell. Biol.20062672736274510.1128/MCB.26.7.2736‑2745.200616537916
     [Google Scholar]
  16. TadesseS. DuckettD.R. MonastyrskyiA. The promise and current status of CDK12/13 inhibition for the treatment of cancer.Future Med. Chem.202113211714110.4155/fmc‑2020‑024033295810
     [Google Scholar]
  17. Chirackal ManavalanA.P. PilarovaK. KlugeM. BartholomeeusenK. RajeckyM. OppeltJ. KhirsariyaP. ParuchK. KrejciL. FriedelC.C. BlazekD. CDK12 controls G1/S progression by regulating RNAPII processivity at core DNA replication genes.EMBO Rep.2019209e4759210.15252/embr.20184759231347271
     [Google Scholar]
  18. DubburyS.J. BoutzP.L. SharpP.A. CDK12 regulates DNA repair genes by suppressing intronic polyadenylation.Nature2018564773414114510.1038/s41586‑018‑0758‑y30487607
     [Google Scholar]
  19. YangB. ChenJ. TengY. YuY-Q. CDK12 promotes cervical cancer progression through enhancing macrophage infiltration.J. Immunol. Res.2021202111410.1155/2021/664588533628849
     [Google Scholar]
  20. HoulesT. LavoieG. NourreddineS. CheungW. Vaillancourt-JeanÉ. GuérinC.M. BouttierM. GrondinB. LinS. Saba-El-LeilM.K. AngersS. MelocheS. RouxP.P. CDK12 is hyperactivated and a synthetic-lethal target in BRAF-mutated melanoma.Nat. Commun.2022131645710.1038/s41467‑022‑34179‑836309522
     [Google Scholar]
  21. GreifenbergA.K. HönigD. PilarovaK. DüsterR. BartholomeeusenK. BöskenC.A. AnandK. BlazekD. GeyerM. Structural and Functional Analysis of the Cdk13/Cyclin K Complex.Cell Rep.201614232033110.1016/j.celrep.2015.12.02526748711
     [Google Scholar]
  22. TellierM. ZaborowskaJ. CaizziL. MohammadE. VelychkoT. SchwalbB. Ferrer-VicensI. BlearsD. NojimaT. CramerP. MurphyS. CDK12 globally stimulates RNA polymerase II transcription elongation and carboxyl-terminal domain phosphorylation.Nucleic Acids Res.202048147712772710.1093/nar/gkaa51432805052
     [Google Scholar]
  23. HarlenK.M. ChurchmanL.S. The code and beyond: transcription regulation by the RNA polymerase II carboxy-terminal domain.Nat. Rev. Mol. Cell Biol.201718426327310.1038/nrm.2017.1028248323
     [Google Scholar]
  24. BöskenC.A. FarnungL. HintermairC. Merzel SchachterM. Vogel-BachmayrK. BlazekD. AnandK. FisherR.P. EickD. GeyerM. The structure and substrate specificity of human Cdk12/Cyclin K.Nat. Commun.201451350510.1038/ncomms450524662513
     [Google Scholar]
  25. Mayor-RuizC. BauerS. BrandM. KozickaZ. SiklosM. ImrichovaH. KaltheunerI.H. HahnE. SeilerK. KorenA. PetzoldG. FellnerM. BockC. MüllerA.C. ZuberJ. GeyerM. ThomäN.H. KubicekS. WinterG.E. Rational discovery of molecular glue degraders via scalable chemical profiling.Nat. Chem. Biol.202016111199120710.1038/s41589‑020‑0594‑x32747809
     [Google Scholar]
  26. EiflerT.T. ShaoW. BartholomeeusenK. FujinagaK. JägerS. JohnsonJ.R. LuoZ. KroganN.J. PeterlinB.M. Cyclin-dependent kinase 12 increases 3′ end processing of growth factor-induced c-FOS transcripts.Mol. Cell. Biol.201535246847810.1128/MCB.01157‑1425384976
     [Google Scholar]
  27. LovénJ. HokeH.A. LinC.Y. LauA. OrlandoD.A. VakocC.R. BradnerJ.E. LeeT.I. YoungR.A. Selective inhibition of tumor oncogenes by disruption of super-enhancers.Cell2013153232033410.1016/j.cell.2013.03.03623582323
     [Google Scholar]
  28. IniguezA.B. StolteB. WangE.J. ConwayA.S. AlexeG. DhariaN.V. KwiatkowskiN. ZhangT. AbrahamB.J. MoraJ. KalevP. LeggettA. ChowdhuryD. BenesC.H. YoungR.A. GrayN.S. StegmaierK. EWS/FLI confers tumor cell synthetic lethality to CDK12 inhibition in ewing sarcoma.Cancer Cell2018332202216.e610.1016/j.ccell.2017.12.00929358035
     [Google Scholar]
  29. DaiW. WuJ. PengX. HouW. HuangH. ChengQ. LiuZ. LuytenW. SchoofsL. ZhouJ. LiuS. CDK12 orchestrates super‐enhancer‐associated CCDC137 transcription to direct hepatic metastasis in colorectal cancer.Clin. Transl. Med.20221210e108710.1002/ctm2.108736254394
     [Google Scholar]
  30. PaculováH. KohoutekJ. The emerging roles of CDK12 in tumorigenesis.Cell Div.2017121710.1186/s13008‑017‑0033‑x29090014
     [Google Scholar]
  31. LiangK. GaoX. GilmoreJ.M. FlorensL. WashburnM.P. SmithE. ShilatifardA. Characterization of human cyclin-dependent kinase 12 (CDK12) and CDK13 complexes in C-terminal domain phosphorylation, gene transcription, and RNA processing.Mol. Cell. Biol.201535692893810.1128/MCB.01426‑1425561469
     [Google Scholar]
  32. TienJ.F. MazloomianA. ChengS.W.G. HughesC.S. ChowC.C.T. CanapiL.T. OloumiA. Trigo-GonzalezG. BashashatiA. XuJ. ChangV.C.D. ShahS.P. AparicioS. MorinG.B. CDK12 regulates alternative last exon mRNA splicing and promotes breast cancer cell invasion.Nucleic Acids Res.201745116698671610.1093/nar/gkx18728334900
     [Google Scholar]
  33. BartkowiakB. GreenleafA.L. Expression, purification, and identification of associated proteins of the full-length hCDK12/CyclinK complex.J. Biol. Chem.201529031786179510.1074/jbc.M114.61222625429106
     [Google Scholar]
  34. RodriguesF. ThumaL. KlämbtC. The regulation of glial-specific splicing of Neurexin IV requires HOW and Cdk12 activity.Development2012139101765177610.1242/dev.07407022461565
     [Google Scholar]
  35. PanzeriV. PieraccioliM. CesariE. de la GrangeP. SetteC. CDK12/13 promote splicing of proximal introns by enhancing the interaction between RNA polymerase II and the splicing factor SF3B1.Nucleic Acids Res.202351115512552610.1093/nar/gkad25837026485
     [Google Scholar]
  36. EkumiK.M. PaculovaH. LenasiT. PospichalovaV. BöskenC.A. RybarikovaJ. BryjaV. GeyerM. BlazekD. BarboricM. Ovarian carcinoma CDK12 mutations misregulate expression of DNA repair genes via deficient formation and function of the Cdk12/CycK complex.Nucleic Acids Res.20154352575258910.1093/nar/gkv10125712099
     [Google Scholar]
  37. KrajewskaM. DriesR. GrassettiA.V. DustS. GaoY. HuangH. SharmaB. DayD.S. KwiatkowskiN. PomavilleM. DoddO. ChipumuroE. ZhangT. GreenleafA.L. YuanG.C. GrayN.S. YoungR.A. GeyerM. GerberS.A. GeorgeR.E. CDK12 loss in cancer cells affects DNA damage response genes through premature cleavage and polyadenylation.Nat. Commun.2019101175710.1038/s41467‑019‑09703‑y30988284
     [Google Scholar]
  38. ElkonR. UgaldeA.P. AgamiR. Alternative cleavage and polyadenylation: extent, regulation and function.Nat. Rev. Genet.201314749650610.1038/nrg348223774734
     [Google Scholar]
  39. LeeS.H. SinghI. TisdaleS. Abdel-WahabO. LeslieC.S. MayrC. Widespread intronic polyadenylation inactivates tumour suppressor genes in leukaemia.Nature2018561772112713110.1038/s41586‑018‑0465‑830150773
     [Google Scholar]
  40. WangB. WangY. WenY. ZhangY.L. NiW.J. TangT.T. CaoJ.Y. YinQ. JiangW. YinD. LiZ.L. LvL.L. LiuB.C. Tubular-specific CDK12 knockout causes a defect in urine concentration due to premature cleavage of the slc12a1 gene.Mol. Ther.202230103300331210.1016/j.ymthe.2022.05.01235581939
     [Google Scholar]
  41. ChoiS.H. MartinezT.F. KimS. DonaldsonC. ShokhirevM.N. SaghatelianA. JonesK.A. CDK12 phosphorylates 4E-BP1 to enable mTORC1-dependent translation and mitotic genome stability.Genes Dev.2019337-841843510.1101/gad.322339.11830819820
     [Google Scholar]
  42. VelásquezC. ChengE. ShudaM. Lee-OesterreichP.J. Pogge von StrandmannL. GritsenkoM.A. JacobsJ.M. MooreP.S. ChangY. Mitotic protein kinase CDK1 phosphorylation of mRNA translation regulator 4E-BP1 Ser83 may contribute to cell transformation.Proc. Natl. Acad. Sci.2016113308466847110.1073/pnas.160776811327402756
     [Google Scholar]
  43. JoshiP.M. SutorS.L. HuntoonC.J. KarnitzL.M. Ovarian cancer-associated mutations disable catalytic activity of CDK12, a kinase that promotes homologous recombination repair and resistance to cisplatin and poly(ADP-ribose) polymerase inhibitors.J. Biol. Chem.2014289139247925310.1074/jbc.M114.55114324554720
     [Google Scholar]
  44. ZhangX. NguyenK.D. RudnickP.A. RoperN. KawalerE. MaityT.K. AwasthiS. GaoS. BiswasR. VenugopalanA. CultraroC.M. FenyöD. GuhaU. Quantitative mass spectrometry to interrogate proteomic heterogeneity in metastatic lung adenocarcinoma and validate a novel somatic mutation CDK12-G879V.Mol. Cell. Proteomics201918462264110.1074/mcp.RA118.00126630617155
     [Google Scholar]
  45. MenghiF. BarthelF.P. YadavV. TangM. JiB. TangZ. CarterG.W. RuanY. ScullyR. VerhaakR.G.W. JonkersJ. LiuE.T. The tandem duplicator phenotype is a prevalent genome-wide cancer configuration driven by distinct gene mutations.Cancer Cell2018342197210.e510.1016/j.ccell.2018.06.00830017478
     [Google Scholar]
  46. JinK. WangS. ZhangY. XiaM. MoY. LiX. LiG. ZengZ. XiongW. HeY. Long non-coding RNA PVT1 interacts with MYC and its downstream molecules to synergistically promote tumorigenesis.Cell. Mol. Life Sci.201976214275428910.1007/s00018‑019‑03222‑131309249
     [Google Scholar]
  47. LiM. LiuY. WeiY. WuC. MengH. NiuW. ZhouY. WangH. WenQ. FanS. LiZ. LiX. ZhouJ. CaoK. XiongW. ZengZ. LiX. QiuY. LiG. ZhouM. Zinc-finger protein YY1 suppresses tumor growth of human nasopharyngeal carcinoma by inactivating c-Myc–mediated microRNA-141 transcription.J. Biol. Chem.2019294156172618710.1074/jbc.RA118.00628130718276
     [Google Scholar]
  48. QuA. JiangC. CaiY. KimJ.H. TanakaN. WardJ.M. ShahY.M. GonzalezF.J. Role of Myc in hepatocellular proliferation and hepatocarcinogenesis.J. Hepatol.201460233133810.1016/j.jhep.2013.09.02424096051
     [Google Scholar]
  49. ZhangY. XiaM. JinK. WangS. WeiH. FanC. WuY. LiX. LiX. LiG. ZengZ. XiongW. Function of the c-Met receptor tyrosine kinase in carcinogenesis and associated therapeutic opportunities.Mol. Cancer20181714510.1186/s12943‑018‑0796‑y29455668
     [Google Scholar]
  50. DavidsonL. MunizL. WestS. 3′ end formation of pre-mRNA and phosphorylation of Ser2 on the RNA polymerase II CTD are reciprocally coupled in human cells.Genes Dev.201428434235610.1101/gad.231274.11324478330
     [Google Scholar]
  51. ZengM. KwiatkowskiN.P. ZhangT. NabetB. XuM. LiangY. QuanC. WangJ. HaoM. PalakurthiS. ZhouS. ZengQ. KirschmeierP.T. MeghaniK. LeggettA.L. QiJ. ShapiroG.I. LiuJ.F. MatulonisU.A. LinC.Y. KonstantinopoulosP.A. GrayN.S. Targeting MYC dependency in ovarian cancer through inhibition of CDK7 and CDK12/13.eLife20187e3903010.7554/eLife.3903030422115
     [Google Scholar]
  52. LiuS. WuJ. LuX. GuoC. ZhengQ. WangY. HuQ. BianS. LuoL. ChengQ. LiuZ. DaiW. Targeting CDK12 obviates the malignant phenotypes of colorectal cancer through the Wnt/β-catenin signaling pathway.Exp. Cell Res.2023428111361310.1016/j.yexcr.2023.11361337100369
     [Google Scholar]
  53. GaoL. WangJ. ChenJ. ZhangX. ZhangM. WangS. ZhaoC. CDK12 promotes the proliferation, migration, and angiogenesis of gastric carcinoma via activating the PI3K/AKT/mTOR signaling pathway.Appl. Biochem. Biotechnol.2023195116913692610.1007/s12010‑023‑04436‑736951936
     [Google Scholar]
  54. LiH. WangJ. YiZ. LiC. WangH. ZhangJ. WangT. NanP. LinF. XuD. QianH. MaF. CDK12 inhibition enhances sensitivity of HER2+ breast cancers to HER2-tyrosine kinase inhibitor via suppressing PI3K/AKT.Eur. J. Cancer20211459210810.1016/j.ejca.2020.11.04533429148
     [Google Scholar]
  55. ZhouC. FengX. YuanF. JiJ. ShiM. YuY. ZhuZ. ZhangJ. Difference of molecular alterations in HER2-positive and HER2-negative gastric cancers by whole-genome sequencing analysis.Cancer Manag. Res.2018103945395410.2147/CMAR.S17271030310315
     [Google Scholar]
  56. LiX. ChatterjeeN. SpirohnK. BoutrosM. BohmannD. Cdk12 is a gene-selective rna polymerase ii kinase that regulates a subset of the transcriptome, including nrf2 target genes.Sci. Rep.2016612145510.1038/srep2145526911346
     [Google Scholar]
  57. FilipponeM.G. GaglioD. BonfantiR. TucciF.A. CeccacciE. PennisiR. BonanomiM. JodiceG. TillhonM. MontaniF. BertalotG. FreddiS. VecchiM. TaglialatelaA. RomanenghiM. RomeoF. BiancoN. MunzoneE. SanguedolceF. VagoG. VialeG. Di FioreP.P. MinucciS. AlberghinaL. ColleoniM. VeronesiP. TosoniD. PeceS. CDK12 promotes tumorigenesis but induces vulnerability to therapies inhibiting folate one-carbon metabolism in breast cancer.Nat. Commun.2022131264210.1038/s41467‑022‑30375‑835550508
     [Google Scholar]
  58. LiuM. RuanX. LiuX. DongW. WangD. YangC. LiuL. WangP. ZhangM. XueY. The mechanism of BUD13 m6A methylation mediated MBNL1-phosphorylation by CDK12 regulating the vasculogenic mimicry in glioblastoma cells.Cell Death Dis.20221312101710.1038/s41419‑022‑05426‑z36463205
     [Google Scholar]
  59. LiuX. LiuY. ChaiW. YanM. LiH. LiJ. SunL. CaoY. LiuQ. SunY. PanH. CDK12 loss inhibits cell proliferation by regulating TBK1 in non-small cell lung cancer cells.Mol. Cell. Probes20237110192310.1016/j.mcp.2023.10192337517598
     [Google Scholar]
  60. ThanindratarnP. DeanD.C. FengW. WeiR. NelsonS.D. HornicekF.J. DuanZ. Cyclin-dependent kinase 12 (CDK12) in chordoma: prognostic and therapeutic value.Eur. Spine J.202029123214322810.1007/s00586‑020‑06543‑z32691223
     [Google Scholar]
  61. Dixon-ClarkeS.E. ElkinsJ.M. ChengS.W.G. MorinG.B. BullockA.N. Structures of the CDK12/CycK complex with AMP-PNP reveal a flexible C-terminal kinase extension important for ATP binding.Sci. Rep.2015511712210.1038/srep1712226597175
     [Google Scholar]
  62. ZhangT. KwiatkowskiN. OlsonC.M. Dixon-ClarkeS.E. AbrahamB.J. GreifenbergA.K. FicarroS.B. ElkinsJ.M. LiangY. HannettN.M. ManzT. HaoM. BartkowiakB. GreenleafA.L. MartoJ.A. GeyerM. BullockA.N. YoungR.A. GrayN.S. Covalent targeting of remote cysteine residues to develop CDK12 and CDK13 inhibitors.Nat. Chem. Biol.2016121087688410.1038/nchembio.216627571479
     [Google Scholar]
  63. WangC. WangH. LieftinkC. du ChatinierA. GaoD. JinG. JinH. BeijersbergenR.L. QinW. BernardsR. CDK12 inhibition mediates DNA damage and is synergistic with sorafenib treatment in hepatocellular carcinoma.Gut202069472773610.1136/gutjnl‑2019‑31850631519701
     [Google Scholar]
  64. FreiK. SchecherS. DaherT. HörnerN. RichterJ. HildebrandU. Inhibition of the Cyclin K‐CDK12 complex induces DNA damage and increases the effect of androgen deprivation therapy in prostate cancer.Int. J. Cancer2023154(6)1082109637916780
     [Google Scholar]
  65. GaoY. ZhangT. TeraiH. FicarroS.B. KwiatkowskiN. HaoM.F. SharmaB. ChristensenC.L. ChipumuroE. WongK. MartoJ.A. HammermanP.S. GrayN.S. GeorgeR.E. Overcoming resistance to the THZ series of covalent transcriptional CDK inhibitors.Cell Chem. Biol.2018252135142.e510.1016/j.chembiol.2017.11.00729276047
     [Google Scholar]
  66. LiuY. HaoM. LeggettA.L. GaoY. FicarroS.B. CheJ. HeZ. OlsonC.M. MartoJ.A. KwiatkowskiN.P. ZhangT. GrayN.S. Discovery of MFH290: A potent and highly selective covalent inhibitor for cyclin-dependent kinase 12/13.J. Med. Chem.202063136708672610.1021/acs.jmedchem.9b0192932502343
     [Google Scholar]
  67. ChengL. ZhouS. ZhouS. ShiK. ChengY. CaiM.C. YeK. LinL. ZhangZ. JiaC. XiangH. ZangJ. ZhangM. YinX. LiY. DiW. ZhuangG. TanL. Dual inhibition of CDK12/CDK13 targets both tumor and immune cells in ovarian cancer.Cancer Res.202282193588360210.1158/0008‑5472.CAN‑22‑022235857807
     [Google Scholar]
  68. JiangB. JiangJ. KaltheunerI.H. IniguezA.B. AnandK. FergusonF.M. FicarroS.B. SeongB.K.A. GreifenbergA.K. DustS. KwiatkowskiN.P. MartoJ.A. StegmaierK. ZhangT. GeyerM. GrayN.S. Structure-activity relationship study of THZ531 derivatives enables the discovery of BSJ-01-175 as a dual CDK12/13 covalent inhibitor with efficacy in Ewing sarcoma.Eur. J. Med. Chem.202122111348110.1016/j.ejmech.2021.11348133945934
     [Google Scholar]
  69. JiangB. GaoY. CheJ. LuW. KaltheunerI.H. DriesR. KalocsayM. BerberichM.J. JiangJ. YouI. KwiatkowskiN. RichingK.M. DanielsD.L. SorgerP.K. GeyerM. ZhangT. GrayN.S. Discovery and resistance mechanism of a selective CDK12 degrader.Nat. Chem. Biol.202117667568310.1038/s41589‑021‑00765‑y33753926
     [Google Scholar]
  70. CrommP.M. SamarasingheK.T.G. HinesJ. CrewsC.M. Addressing Kinase-Independent Functions of Fak via PROTAC-Mediated Degradation.J. Am. Chem. Soc.201814049170191702610.1021/jacs.8b0800830444612
     [Google Scholar]
  71. NiuT. LiK. JiangL. ZhouZ. HongJ. ChenX. DongX. HeQ. CaoJ. YangB. ZhuC.L. Noncovalent CDK12/13 dual inhibitors-based PROTACs degrade CDK12-Cyclin K complex and induce synthetic lethality with PARP inhibitor.Eur. J. Med. Chem.202222811401210.1016/j.ejmech.2021.11401234864331
     [Google Scholar]
  72. YangJ. ChangY. TienJ.C.Y. WangZ. ZhouY. ZhangP. HuangW. VoJ. ApelI.J. WangC. ZengV.Z. ChengY. LiS. WangG.X. ChinnaiyanA.M. DingK. Discovery of a highly potent and selective dual PROTAC Degrader of CDK12 and CDK13.J. Med. Chem.20226516110661108310.1021/acs.jmedchem.2c0038435938508
     [Google Scholar]
  73. SłabickiM. KozickaZ. PetzoldG. LiY.D. ManojkumarM. BunkerR.D. DonovanK.A. SieversQ.L. KoeppelJ. SuchytaD. SperlingA.S. FinkE.C. GasserJ.A. WangL.R. CorselloS.M. SellarR.S. JanM. GillinghamD. SchollC. FröhlingS. GolubT.R. FischerE.S. ThomäN.H. EbertB.L. The CDK inhibitor CR8 acts as a molecular glue degrader that depletes cyclin K.Nature2020585782429329710.1038/s41586‑020‑2374‑x32494016
     [Google Scholar]
  74. LvL. ChenP. CaoL. LiY. ZengZ. CuiY. WuQ. LiJ. WangJ.H. DongM.Q. QiX. HanT. Discovery of a molecular glue promoting CDK12-DDB1 interaction to trigger cyclin K degradation.eLife20209e5999410.7554/eLife.5999432804079
     [Google Scholar]
  75. HoulesT. BoucherJ. LavoieG. MacLeodG. LinS. AngersS. RouxP.P. The CDK12 inhibitor SR-4835 functions as a molecular glue that promotes cyclin K degradation in melanoma.Cell Death Discov.20239145910.1038/s41420‑023‑01754‑x38104154
     [Google Scholar]
  76. DieterS.M. SieglC. CodóP.L. HuertaM. Ostermann-ParuchaA.L. SchulzE. ZowadaM.K. MartinS. LaaberK. NowrouziA. BlatterM. KrethS. WestermannF. BennerA. UhrigU. PutzkerK. LewisJ. HaegebarthA. MumbergD. HoltonS.J. WeiskeJ. ToepperL.M. ScheibU. SiemeisterG. BallC.R. KusterB. StoehrG. HahneH. JohannesS. LangeM. HerbstF. GlimmH. Degradation of CCNK/CDK12 is a druggable vulnerability of colorectal cancer.Cell Rep.202136310939410.1016/j.celrep.2021.10939434289372
     [Google Scholar]
  77. ItoM. TanakaT. ToitaA. UchiyamaN. KokuboH. MorishitaN. KleinM.G. ZouH. MurakamiM. KondoM. SameshimaT. ArakiS. EndoS. KawamotoT. MorinG.B. AparicioS.A. NakanishiA. MaezakiH. ImaedaY. Discovery of 3-Benzyl-1-( trans -4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-1-arylurea derivatives as novel and selective cyclin-dependent kinase 12 (CDK12) Inhibitors.J. Med. Chem.201861177710772810.1021/acs.jmedchem.8b0068330067358
     [Google Scholar]
  78. BajramiI. FrankumJ.R. KondeA. MillerR.E. RehmanF.L. BroughR. CampbellJ. SimsD. RafiqR. HooperS. ChenL. KozarewaI. AssiotisI. FenwickK. NatrajanR. LordC.J. AshworthA. Genome-wide profiling of genetic synthetic lethality identifies CDK12 as a novel determinant of PARP1/2 inhibitor sensitivity.Cancer Res.201474128729710.1158/0008‑5472.CAN‑13‑254124240700
     [Google Scholar]
  79. ZhangL. ZhenY. FengL. LiZ. LuY. WangG. OuyangL. Discovery of a novel dual-target inhibitor of CDK12 and PARP1 that induces synthetic lethality for treatment of triple-negative breast cancer.Eur. J. Med. Chem.202325911564810.1016/j.ejmech.2023.11564837478560
     [Google Scholar]
  80. LinS. JiangQ. HuangX. XuJ. WuL. LiuY. Synthesis of novel dual target inhibitors of CDK12 and PARP1 and their antitumor activities in HER2-positive breast cancers.ACS Omega2023828255742558110.1021/acsomega.3c0291237483237
     [Google Scholar]
  81. van der NoordV.E. van der StelW. LouwerensG. VerhoevenD. KuikenH.J. LieftinkC. GranditsM. EckerG.F. BeijersbergenR.L. BouwmanP. Le DévédecS.E. van de WaterB. Systematic screening identifies ABCG2 as critical factor underlying synergy of kinase inhibitors with transcriptional CDK inhibitors.Breast Cancer Res.20232515110.1186/s13058‑023‑01648‑x37147730
     [Google Scholar]
  82. QueredaV. BayleS. VenaF. FrydmanS.M. MonastyrskyiA. RoushW.R. DuckettD.R. Therapeutic targeting of CDK12/CDK13 in triple-negative breast cancer.Cancer Cell2019365545558.e710.1016/j.ccell.2019.09.00431668947
     [Google Scholar]
  83. ToyoshimaM. HowieH.L. ImakuraM. WalshR.M. AnnisJ.E. ChangA.N. FrazierJ. ChauB.N. LobodaA. LinsleyP.S. ClearyM.A. ParkJ.R. GrandoriC. Functional genomics identifies therapeutic targets for MYC-driven cancer.Proc. Natl. Acad. Sci.2012109249545955010.1073/pnas.112111910922623531
     [Google Scholar]
  84. BaylesI. KrajewskaM. PontiusW.D. SaiakhovaA. MorrowJ.J. BartelsC. LuJ. FaberZ.J. FedorovY. HongE.S. KarnutaJ.M. RubinB. AdamsD.J. GeorgeR.E. ScacheriP.C. Ex vivo screen identifies CDK12 as a metastatic vulnerability in osteosarcoma.J. Clin. Invest.2019129104377439210.1172/JCI12771831498151
     [Google Scholar]
  85. Del NagroC.J. ChoiJ. XiaoY. RangellL. MohanS. PanditaA. ZhaJ. JacksonP.K. O’BrienT. Chk1 inhibition in p53-deficient cell lines drives rapid chromosome fragmentation followed by caspase-independent cell death.Cell Cycle201413230331410.4161/cc.2705524247149
     [Google Scholar]
  86. AntonarakisE.S. PhimisterE.G. Cyclin-dependent kinase 12, immunity, and prostate cancer.N. Engl. J. Med.2018379111087108910.1056/NEJMcibr180877230207914
     [Google Scholar]
  87. PanE. CabalA. Javier-DesLogesJ. PatelD. PanianJ. LeeS. ShayaJ. NonatoT. XuX. StewartT. RoseB. ShabaikA. CohenE. KurzrockR. TamayoP. McKayR.R. Analysis of CDK12 alterations in a pan‐cancer database.Cancer Med.202211375376310.1002/cam4.448334898046
     [Google Scholar]
  88. ZhangG. LanB. ZhangX. LinM. LiuY. ChenJ. GuoF. AR-A014418 regulates intronic polyadenylation and transcription of PD-L1 through inhibiting CDK12 and CDK13 in tumor cells.J. Immunother. Cancer2023115e00648310.1136/jitc‑2022‑00648337164450
     [Google Scholar]
  89. HossainD.M.S. JavaidS. CaiM. ZhangC. SawantA. HintonM. SatheM. GreinJ. BlumenscheinW. PinheiroE.M. ChackerianA. Dinaciclib induces immunogenic cell death and enhances anti-PD1–mediated tumor suppression.J. Clin. Invest.2018128264465410.1172/JCI9458629337311
     [Google Scholar]
  90. WuY.M. CieślikM. LonigroR.J. VatsP. ReimersM.A. CaoX. NingY. WangL. KunjuL.P. de SarkarN. HeathE.I. ChouJ. FengF.Y. NelsonP.S. de BonoJ.S. ZouW. MontgomeryB. AlvaA. RobinsonD.R. ChinnaiyanA.M. Inactivation of CDK12 delineates a distinct immunogenic class of advanced prostate cancer.Cell2018173717701782.e1410.1016/j.cell.2018.04.03429906450
     [Google Scholar]
  91. GongoraA.B.L. MarshallC.H. VelhoP.I. LopesC.D.H. MarinJ.F. CamargoA.A. BastosD.A. AntonarakisE.S. Extreme responses to a combination of DNA-damaging therapy and immunotherapy in cdk12-altered metastatic castration-resistant prostate cancer: A potential therapeutic vulnerability.Clin. Genitourin. Cancer202220218318810.1016/j.clgc.2021.11.01535027313
     [Google Scholar]
  92. JiJ. ZhouC. WuJ. CaiQ. ShiM. ZhangH. YuY. ZhuZ. ZhangJ. Expression pattern of CDK12 protein in gastric cancer and its positive correlation with CD8 + cell density and CCL12 expression.Int. J. Med. Sci.20191681142114810.7150/ijms.3454131523177
     [Google Scholar]
  93. ZhangS.Y. SongX.Y. LiY. YeL.L. ZhouQ. YangW.B. Tumor-associated macrophages: A promising target for a cancer immunotherapeutic strategy.Pharmacol. Res.202016110511110.1016/j.phrs.2020.10511133065284
     [Google Scholar]
  94. KanakkantharaA. KurmiK. EkstromT.L. HouX. PurfeerstE.R. HeinzenE.P. CorreiaC. HuntoonC.J. O’BrienD. Wahner HendricksonA.E. DowdyS.C. LiH. ObergA.L. HitosugiT. KaufmannS.H. WerohaS.J. KarnitzL.M. BRCA1 deficiency upregulates NNMT, which reprograms metabolism and sensitizes ovarian cancer cells to mitochondrial metabolic targeting agents.Cancer Res.201979235920592910.1158/0008‑5472.CAN‑19‑140531619387
     [Google Scholar]
  95. RanaS. MallareddyJ.R. SinghS. BogheanL. NatarajanA. Inhibitors, PROTACs and molecular glues as diverse therapeutic modalities to target cyclin-dependent kinase.Cancers20211321550610.3390/cancers1321550634771669
     [Google Scholar]
  96. RobbC.M. KourS. ContrerasJ.I. AgarwalE. BargerC.J. RanaS. SonawaneY. NeilsenB.K. TaylorM. KizhakeS. ThakareR.N. ChowdhuryS. WangJ. BlackJ.D. HollingsworthM.A. BrattainM.G. NatarajanA. Characterization of CDK(5) inhibitor, 20-223 (aka CP668863) for colorectal cancer therapy.Oncotarget2018945216523210.18632/oncotarget.2374929435174
     [Google Scholar]
  97. HanX. WangC. QinC. XiangW. Fernandez-SalasE. YangC.Y. WangM. ZhaoL. XuT. ChinnaswamyK. DelpropostoJ. StuckeyJ. WangS. Discovery of ARD-69 as a highly potent proteolysis targeting chimera (PROTAC) degrader of Androgen Receptor (AR) for the treatment of prostate cancer.J. Med. Chem.201962294196410.1021/acs.jmedchem.8b0163130629437
     [Google Scholar]
  98. HuJ. HuB. WangM. XuF. MiaoB. YangC.Y. WangM. LiuZ. HayesD.F. ChinnaswamyK. DelpropostoJ. StuckeyJ. WangS. Discovery of ERD-308 as a highly potent proteolysis targeting chimera (PROTAC) degrader of Estrogen Receptor (ER).J. Med. Chem.20196231420144210.1021/acs.jmedchem.8b0157230990042
     [Google Scholar]
/content/journals/ccdt/10.2174/0115680096307629240611104728
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Development of CDK12 as a Cancer Therapeutic Target and Related Inhibitors
Curr. Cancer Drug Targets< 25, 749 (2025); https://doi.org/10.2174/0115680096307629240611104728
/content/journals/ccdt/10.2174/0115680096307629240611104728
/content/journals/ccdt/10.2174/0115680096307629240611104728
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  • Article Type:     Review Article
Keyword(s): Cancer; cancer biomarker; CDK12; inhibitors; molecular structure; PROTAC; signaling pathways

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