449
Views
3
CrossRef citations to date
0
Altmetric
Review

A patent review of selective CDK9 inhibitors in treating cancer

, , , , , & show all
Pages 309-322 | Received 21 Feb 2023, Accepted 25 Apr 2023, Published online: 05 May 2023

References

  • Roskoski R. Cyclin-dependent protein serine/threonine kinase inhibitors as anticancer drugs. Pharmacol Res. 2019;139:471–488.
  • Panagiotou E, Gomatou G, Trontzas IP, et al. Cyclin-dependent kinase (CDK) inhibitors in solid tumors: a review of clinical trials. Clin Transl Oncol. 2022;24(2):161–192. DOI:10.1007/s12094-021-02688-5
  • Zhang M, Zhang L, Hei R, et al. CDK inhibitors in cancer therapy, an overview of recent development. Am J Cancer Res. 2021;11(5):1913–1935.
  • Lapenna S, Giordano A. Cell cycle kinases as therapeutic targets for cancer. Nat Rev Drug Discov. 2009;8(7):547–566.
  • Cheng W, Yang Z, Wang S, et al. Recent development of CDK inhibitors: an overview of CDK/inhibitor co-crystal structures. Eur J Med Chem. 2019;164:615–639.
  • Bradner JE, Hnisz D, Young RA. Transcriptional addiction in cancer. Cell. 2017;168(4):629–643.
  • Galbraith MD, Bender H, Espinosa JM. Therapeutic targeting of transcriptional cyclin-dependent kinases. Transcription. 2019;10(2):118–136.
  • Yu Z, Du JY, Zhao Y, et al. A novel kinase inhibitor, LZT-106, downregulates Mcl-1 and sensitizes colorectal cancer cells to BH3 mimetic ABT-199 by targeting CDK9 and GSK-3 beta signaling. Cancer Lett. 2021;498:31–41.
  • Danilov A, Rowland T, Paiva C, et al. Selective targeting cyclin-dependent kinase-9 (CDK9) antagonizes survival of neoplastic B-cells via deregulation of c-MYC and MCL-1. Leuk Lymphoma. 2017;58:25–26.
  • Huang WL, Abudureheman T, Xia J, et al. CDK9 inhibitor induces the apoptosis of B-Cell acute lymphocytic leukemia by inhibiting c-Myc-mediated glycolytic metabolism. Front Cell Dev Biol. 2021;9:641271.
  • Zhang HH, Pandey S, Travers M, et al. Targeting CDK9 reactivates epigenetically silenced genes in cancer. Cell. 2018;175(5):1244. DOI:10.1016/j.cell.2018.09.051
  • Bhurta D, Bharate SB. Analyzing the scaffold diversity of cyclin-dependent kinase inhibitors and revisiting the clinical and preclinical pipeline. Med Res Rev. 2022;42(2):654–709.
  • Asghar U, Witkiewicz AK, Turner NC, et al. The history and future of targeting cyclin-dependent kinases in cancer therapy. Nat Rev Drug Discov. 2015;14(2):130–146. DOI:10.1038/nrd4504
  • Wu T, Qin Z, Tian Y, et al. Recent developments in the biology and medicinal chemistry of CDK9 inhibitors: an update. J Med Chem. 2020;63(22):13228–13257. DOI:10.1021/acs.jmedchem.0c00744
  • Alsfouk A. Small molecule inhibitors of cyclin-dependent kinase 9 for cancer therapy. J Enzyme Inhib Med Chem. 2021;36(1):693–706.
  • Huang Z, Wang T, Wang C, et al. CDK9 inhibitors in cancer research. RSC Med Chem. 2022;13(6):688–710. DOI:10.1039/D2MD00040G
  • Bacon CW, D’Orso I. CDK9: a signaling hub for transcriptional control. Transcription. 2019;10(2):57–75.
  • Mandal R, Becker S, Strebhardt K. Targeting CDK9 for anti-cancer therapeutics. Cancers (Basel). 2021;13(9). DOI:10.3390/cancers13092181
  • Mbonye UR, Gokulrangan G, Datt M, et al. Phosphorylation of CDK9 at Ser175 enhances HIV transcription and is a marker of activated P-TEFb in CD4(+) T lymphocytes. PLOS Pathog. 2013;9(5):e1003338. DOI:10.1371/journal.ppat.1003338
  • Clopper KC, Taatjes DJ. Chemical inhibitors of transcription-associated kinases. Curr Opin Chem Biol. 2022;70:102186.
  • Troiani M, Colucci M, D’Ambrosio M, et al. Single-cell transcriptomics identifies Mcl-1 as a target for senolytic therapy in cancer. Nat Commun. 2022;13(1):2177. DOI:10.1038/s41467-022-29824-1
  • Hsieh MJ, Hsieh YH, Lin CW, et al. Transcriptional regulation of Mcl-1 plays an important role of cellular protective effector of vincristine-triggered autophagy in oral cancer cells. Expert Opin Ther Targets. 2015;19(4):455–470. DOI:10.1517/14728222.2014.998200
  • Jin YP, Qiu JP, Lu XF, et al. C-MYC inhibited ferroptosis and promoted immune evasion in ovarian cancer cells through NCOA4 mediated ferritin autophagy. Cells. 2022;11(24):4127. DOI:10.3390/cells11244127.
  • Park M, Cho JH, Moon B, et al. CDK9 inhibitors downregulate DKK1 expression to suppress the metastatic potential of HCC cells. Genes Genomics. 2023;45(3):285–293. DOI:10.1007/s13258-022-01351-9
  • Xu Z, Zhang B, Liu Z, et al. Design, synthesis and anticancer evaluation of selective 2,4-disubstituted pyrimidine CDK9 inhibitors. Eur J Med Chem. 2022;244:114875.
  • Wang XR, Liu XY, Huang JH, et al. Discovery of 2H-benzo[b][1,4]oxazin-3(4H)-one derivatives as potent and selective CDK9 inhibitors that enable transient target engagement for the treatment of hematologic malignancies. Eur J Med Chem. 2022;238:114461.
  • Passalacqua MI, Rizzo G, Santarpia MC, et al. Why is survival with triple negative breast cancer so low? insights and talking points from preclinical and clinical research. Expert Opin Investig Drugs. 2022;31(12):1291–1310. DOI:10.1080/13543784.2022.2159805
  • Cheng S, Yang GJ, Wang W, et al. Discovery of a tetrahydroisoquinoline-based CDK9-cyclin T1 protein-protein interaction inhibitor as an anti-proliferative and anti-migration agent against triple-negative breast cancer cells. Genes Dis. 2022;9(6):1674–1688. DOI:10.1016/j.gendis.2021.06.005
  • Brisard D, Eckerdt F, Marsh LA, et al. Antineoplastic effects of selective CDK9 inhibition with atuveciclib on cancer stem-like cells in triple-negative breast cancer. Oncotarget. 2018;9(99):37305–37318. DOI:10.18632/oncotarget.26468
  • Winter JM, Mustafa EH, Wang SD, et al. Novel and highly selective CDK9 inhibitors suppress proliferation of triple negative breast cancer (TNBC) cells in vitro. Cancer Res. 2019;79(13):4433. DOI:10.1158/1538-7445.AM2019-4433
  • Cheng SS, Qu YQ, Wu J, et al. Inhibition of the CDK9-cyclin T1 protein-protein interaction as a new approach against triple-negative breast cancer. Acta Pharm Sin B. 2022;12(3):1390–1405. DOI:10.1016/j.apsb.2021.10.024
  • Wei D, Wang HL, Zeng QH, et al. Discovery of potent and selective CDK9 degraders for targeting transcription regulation in triple-negative breast cancer. J Med Chem. 2021;64(19):14822–14847. DOI:10.1021/acs.jmedchem.1c01350
  • Zhao W, Zhang L, Zhang Y, et al. The CDK inhibitor AT7519 inhibits human glioblastoma cell growth by inducing apoptosis, pyroptosis and cell cycle arrest. Cell Death Dis. 2023;14(1):11. DOI:10.1038/s41419-022-05528-8
  • Chin L, Meyerson M, Aldape K, et al. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature. 2008;455(7216):1061–1068.
  • El Atat O, Naser R, Abdelkhalek M, et al. Molecular targeted therapy: a new avenue in glioblastoma treatment. Oncol Lett. 2023;25(2):46. DOI:10.3892/ol.2022.13632
  • Ranjan A, Pang Y, Butler M, et al. Targeting CDK9 for the treatment of glioblastoma. Cancers (Basel). 2021;13(12):3039. DOI:10.3390/cancers13123039
  • Qiu Z, Zhao L, Shen JZ, et al. Transcription elongation machinery is a druggable dependency and potentiates immunotherapy in glioblastoma stem cells. Cancer Discov. 2022;12(2):502–521. DOI:10.1158/2159-8290.CD-20-1848
  • Xie Q, Wu Q, Kim L, et al. RBPJ maintains brain tumor-initiating cells through CDK9-mediated transcriptional elongation. J Clin Invest. 2016;126(7):2757–2772. DOI:10.1172/JCI86114
  • Aurilio G, Cimadamore A, Mazzucchelli R, et al. Androgen receptor signaling pathway in prostate cancer: from genetics to clinical applications. Cells. 2020;9(12):2653.
  • Gao X, Liang J, Wang L, et al. Phosphorylation of the androgen receptor at Ser81 is co-sustained by CDK1 and CDK9 and leads to AR-mediated transactivation in prostate cancer. Mol Oncol. 2021;15(7):1901–1920. DOI:10.1002/1878-0261.12968
  • Gordon V, Bhadel S, Wunderlich W, et al. CDK9 regulates AR promoter selectivity and cell growth through serine 81 phosphorylation. Mol Endocrinol. 2010;24(12):2267–2280. DOI:10.1210/me.2010-0238
  • Pallasaho S, Gondane A, Kuivalainen A, et al. Castration-resistant prostate cancer cells are dependent on the high activity of CDK7. J Cancer Res Clin Oncol. 2022. doi: 10.1007/s00432-022-04475-3.
  • Richters A, Doyle SK, Freeman DB, et al. Modulating androgen receptor-driven transcription in prostate cancer with selective CDK9 inhibitors. Cell Chem Biol. 2021;28(2):134–147. DOI:10.1016/j.chembiol.2020.10.001
  • Amrhein JA, Beyett TS, Feng WW, et al. Macrocyclization of quinazoline-based EGFR inhibitors leads to exclusive mutant selectivity for EGFR L858R and Del19. J Med Chem. 2022;65(23):15679–15697. DOI:10.1021/acs.jmedchem.2c01041
  • Obst-Sander U, Ricci A, Kuhn B, et al. Discovery of novel allosteric EGFR L858R inhibitors for the treatment of non-small-cell lung cancer as a single agent or in combination with osimertinib. J Med Chem. 2022;65(19):13052–13073. DOI:10.1021/acs.jmedchem.2c00893
  • Xu L, Xu B, Wang JS, et al. Recent advances of novel fourth generation EGFR inhibitors in overcoming C797S mutation of lung cancer therapy. Eur J Med Chem. 2023;245:114900.
  • Yang LH, Zhou F, Zhuang Y, et al. Acetyl-bufalin shows potent efficacy against non-small-cell lung cancer by targeting the CDK9/STAT3 signalling pathway. Br J Cancer. 2021;124(3):645–657. DOI:10.1038/s41416-020-01135-6
  • Padmanabhan J, Saha B, Powell C, et al. Inhibitors targeting CDK9 show high efficacy against osimertinib and AMG510 resistant lung adenocarcinoma cells. Cancers (Basel). 2021;13(15):3906. DOI:10.3390/cancers13153906
  • Pollyea DA, Bixby D, Perl A, et al. NCCN guidelines insights: acute myeloid leukemia, version 2.2021. J Natl Compr Canc Netw. 2021;19(1):16–27. DOI:10.6004/jnccn.2021.0002
  • Xu J, Li H, Wang X, et al. Discovery of coumarin derivatives as potent and selective cyclin-dependent kinase 9 (CDK9) inhibitors with high antitumour activity. Eur J Med Chem. 2020;200:112424.
  • Wang J, Li T, Zhao T, et al. Design of wogonin-inspired selective cyclin-dependent kinase 9 (CDK9) inhibitors with potent in vitro and in vivo antitumor activity. Eur J Med Chem. 2019;178:782–801.
  • Zhang J, Wang Y, Yin C, et al. Artesunate improves venetoclax plus cytarabine AML cell targeting by regulating the Noxa/Bim/Mcl-1/p-Chk1 axis. Cell Death Dis. 2022;13(4):379. DOI:10.1038/s41419-022-04810-z
  • Liu F, Zhao Q, Su Y, et al. Cotargeting of Bcl-2 and Mcl-1 shows promising antileukemic activity against AML cells including those with acquired cytarabine resistance. Exp Hematol. 2022;105:39–49.
  • Fernandez-Marrero Y, Spinner S, Kaufmann T, et al. Survival control of malignant lymphocytes by anti-apoptotic MCL-1. Leukemia. 2016;30(11):2152–2159. DOI:10.1038/leu.2016.213
  • Fiskus W, Manshouri T, Birdwell C, et al. Efficacy of CDK9 inhibition in therapy of post-myeloproliferative neoplasm (MPN) secondary (s) AML cells. Blood Cancer J. 2022;12(1):23. DOI:10.1038/s41408-022-00618-4
  • Sher S, Whipp E, Walker J, et al. VIP152 is a selective CDK9 inhibitor with pre-clinical in vitro and in vivo efficacy in chronic lymphocytic leukemia. Leukemia. 2023;37(2):326–338. DOI:10.1038/s41375-022-01758-z
  • He XL, Hu YH, Chen JM, et al. SNS-032 attenuates liver fibrosis by anti-active hepatic stellate cells via inhibition of cyclin dependent kinase 9. Front Pharmacol. 2022;13:1016552.
  • Parvathareddy SK, Siraj AK, Masoodi T, et al. Cyclin-dependent kinase 9 (CDK9) predicts recurrence in Middle Eastern epithelial ovarian cancer. J Ovarian Res. 2021;14(1):69. DOI:10.1186/s13048-021-00827-8
  • Li J, Zhi X, Chen S, et al. CDK9 inhibitor CDKI-73 is synergetic lethal with PARP inhibitor olaparib in BRCA1 wide-type ovarian cancer. Am J Cancer Res. 2020;10(4):1140–1155.
  • Guhan SM, Shaughnessy M, Rajadurai A, et al. The molecular context of vulnerability for CDK9 suppression in triple wild-type melanoma. J Invest Dermatol. 2021;141(8):2018–2027. DOI:10.1016/j.jid.2020.12.035
  • Zhang Y, Hou J, Shi S, et al. CSN6 promotes melanoma proliferation and metastasis by controlling the UBR5-mediated ubiquitination and degradation of CDK9. Cell Death Dis. 2021;12(1):118. DOI:10.1038/s41419-021-03398-0
  • Fleischmann M, Mandal R, Kostova I, et al. Prognostic impact of caspase-8, CDK9 and phospho-CDK9 (Thr 186) expression in patients with uterine cervical cancer treated with definitive chemoradiation and brachytherapy. Cancers (Basel). 2022;14(22):5500. DOI:10.3390/cancers14225500
  • Mandal R, Raab M, Rodel F, et al. The non-apoptotic function of caspase-8 in negatively regulating the CDK9-mediated Ser2 phosphorylation of RNA polymerase II in cervical cancer. Cell Mol Life Sci. 2022;79(12):597. DOI:10.1007/s00018-022-04598-3
  • Ma H, Seebacher NA, Hornicek FJ, et al. Cyclin-dependent kinase 9 (CDK9) is a novel prognostic marker and therapeutic target in osteosarcoma. EBioMedicine. 2019;39:182–193.
  • Borowczak J, Szczerbowski K, Maniewski M, et al. The prognostic role of CDK9 in bladder cancer. Cancers (Basel). 2022;14(6):1492. DOI:10.3390/cancers14061492
  • Anshabo AT, Milne R, Wang SD, et al. CDK9: a comprehensive review of its biology, and its role as a potential target for anti-cancer agents. Front Oncol. 2021;11:678559.
  • Lucking U, Scholz A, Lienau P, et al. Identification of atuveciclib (BAY 1143572), the first highly selective, clinical PTEFB/CDK9 inhibitor for the treatment of cancer. ChemMedchem. 2017;12(21):1776–1793. DOI:10.1002/cmdc.201700447
  • Lucking U, Kosemund D, Bohnke N, et al. Changing for the better: discovery of the highly potent and selective CDK9 inhibitor VIP152 suitable for once weekly intravenous dosing for the treatment of cancer. J Med Chem. 2021;64(15):11651–11674. DOI:10.1021/acs.jmedchem.1c01000
  • Barlaam B, De Savi C, Dishington A, et al. Discovery of a series of 7-azaindoles as potent and highly selective CDK9 inhibitors for transient target engagement. J Med Chem. 2021;64(20):15189–15213. DOI:10.1021/acs.jmedchem.1c01249
  • Cidado J, Boiko S, Proia T, et al. AZD4573 is a highly selective CDK9 inhibitor that suppresses MCL-1 and induces apoptosis in hematologic cancer cells. Clin Cancer Res. 2020;26(4):922–934. DOI:10.1158/1078-0432.CCR-19-1853
  • Zhao Z, Wu S, Liu Y, et al., inventors; Shanghai Haiyan Pharmaceutical Technology Co., Ltd. Yangtze River Pharmaceutical Group Co., Ltd, assignee. Substituted bis(pyridin-2-yl)amine derivative, composition thereof and medical use thereof patent WO2022078309. 2022.
  • Liu Q, Liu J, Wu Y, et al., inventors; Hefei Institutes of Physical Science, Chinese Academy of Sciences, assignee. Preparation of dihydroisoquinolone and isoindolinone derivatives as CDK9 inhibitors patent CN114516856. 2022.
  • Wang S, Long Y, Yu M, et al., inventors; Aucentra Therapeutics Pty Ltd, assignee. Preparation of derivatives of 4-(imidazo[1,2-a]pyridin-3-yl)-N-(pyridin-3-yl)pyrimidin-2-amine for treating proliferative diseases and conditions patent WO2021072475. 2021.
  • Li Z, Bian J, Wu T, et al., inventors; China Pharmaceutical University, assignee. Preparation and application of aminopyrimidine derivative selectively targeting cdk9 patent WO2023005280. 2023.
  • Bian J, Li Z, Wu T, et al., inventors; China Pharmaceutical University, assignee. Preparation method for and application of novel cdk9 inhibitor having macrocyclic skeleton structure patent WO2023005281. 2023.
  • Barlaam B, Casella R, Cidado J, et al. Discovery of AZD4573, a potent and selective inhibitor of CDK9 that enables short duration of target engagement for the treatment of hematological malignancies. J Med Chem. 2020;63(24):15564–15590. DOI:10.1021/acs.jmedchem.0c01754
  • Boiko S, Proia T, San Martin M, et al. Transient CDK9 inhibition with AZD4573 modulates Bfl-1 in preclinical lymphoma models. Cancer Res. 2019;79(13):2500. DOI:10.1158/1538-7445.AM2019-2500
  • Cidado J, Proia T, Boiko S, et al. AZD4573, a novel CDK9 inhibitor, rapidly induces cell death in hematological tumor models through depletion of Mcl1. Cancer Res. 2018;78(13):310. DOI:10.1158/1538-7445.AM2018-310
  • U.S. National library of medicine: ClinicalTrials.Gov. Available from https://www.clinicaltrials.gov . [cited Feb 19, 2023]
  • Wang Z, Zhang Y, Mu Y, et al., inventors; CSPC Zhongqi Pharmaceutical Technology (Shijiazhuang) Co., Ltd, assignee. Preparation of the heterocyclic analogues and their application as cyclin-dependent kinase 9 inhibitors patent WO2021115335. 2021.
  • Zheng S, Xie C, Zheng M, et al., inventors; Suzhou Alphama Biotech Co., Ltd, assignee. Polycyclic amide derivatives as CDK9 inhibitors, its preparation method, and its application in treating of cancer patent CN113149996. 2021.
  • Zheng S, Xie C, Zheng M, et al., inventors; Suzhou Alphama Biotech Co., Ltd. assignee. Preparation of ((aryl)chloropyridyl)acetamides as CDK inhibitor patent CN113173924. 2021.
  • Wan H, Zha C, Wang Y, et al., inventors; Shanghai Ringene Biopharma Co., Ltd. Shanghai Lingji Biological Technology Co., Ltd, assignee. Preparation of pyrimidine-based compounds having CDK kinase inhibitory activity, pharmaceutical compositions and its application patent CN114605390. 2022.
  • Lu L, Shetty R, Combs AP, et al. Prelude therapeutics incorporated, assignee. Preparation of indazolyl-pyrimidines and related heterocycles as CDK inhibitors and their use as pharmaceuticals patent US20210070761. 2021. inventors
  • Zhao Z, Wu S, Hua M, et al., inventors; Shanghai Haiyan Pharmaceutical Technology Co., Ltd. Yangtze River Pharmaceutical Group Co., Ltd, assignee. Substituted pyrazolo[1,5-a]pyrimidine-7-amine derivative, compositions and medical use patent WO2022156779. 2022.
  • Mikochik P, Vacca J, Freeman D, et al., inventors; Kronos Bio, Inc., assignee. Preparation of pyrazolopyrimidines, compositions with them, as CDK9 activity modulators useful in treatment of CDK9-mediated diseases patent US20200131189. 2020.
  • Huang Y, Jiang C, Yu H, et al., inventors; Shenzhen Bay Laboratory Pingshan Biomedical R&D and Transformation Center Peking University Shenzhen Graduate School Shenzhen Rongxin Biotechnology Co., Ltd., assignee. Compound as CDK9 kinase inhibitor and preparation and pharmaceutical composition thereof patent CN112125911. 2020.
  • Li Y, Quan Y, Wang Y, et al., inventors; Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences, assignee. Preparation of pyrrolo[2,3-d]pyrimidine derivatives as CDK4, 6 or 9 inhibitors and used as antitumor agents patent CN112375081. 2021.
  • Liu Y, Xu Z, Hu L, et al., inventors; Medshine Discovery Inc, assignee. Azaindole pyrazole compounds as CDK9 inhibitors patent WO2020259556. 2020.
  • Spyvee MR, Kallenbach JM, Gupta A, et al., inventors; Reverie Labs, Inc, assignee. Naphtho[2,1-d]thiazole derivatives, compositions thereof and methods of treating disorders and their preparation patent WO2021102410. 2021.
  • Han X, Song N, Saidahmatov A, et al. Rational design and development of novel CDK9 inhibitors for the treatment of acute myeloid leukemia. J Med Chem. 2021;64(19):14647–14663. DOI:10.1021/acs.jmedchem.1c01148
  • Verma J, Khedkar VM, Coutinho EC. 3D-QSAR in drug design–a review. Curr Top Med Chem. 2010;10(1):95–115.
  • Moffat JG, Rudolph J, Bailey D. Phenotypic screening in cancer drug discovery - past, present and future. Nat Rev Drug Discov. 2014;13(8):588–602.
  • Butera JA. Phenotypic screening as a strategic component of drug discovery programs targeting novel antiparasitic and antimycobacterial agents: an editorial miniperspectives series on phenotypic screening for antiinfective targets. J Med Chem. 2013;56(20):7715–7718.
  • Garber K. The PROTAC gold rush. Nat Biotechnol. 2022;40(1):12–16.
  • Li J, Liu T, Song Y, et al. Discovery of small-molecule degraders of the CDK9-cyclin T1 complex for targeting transcriptional addiction in prostate cancer. J Med Chem. 2022;65(16):11034–11057. DOI:10.1021/acs.jmedchem.2c00257

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.