Inhibitors of Cyclin-Dependent Kinases: Types and Their Mechanism of Action

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2021 Apr 3

PMID 33802080

Citations 27

Authors

Pawel Lukasik

Irena Baranowska-Bosiacka

Katarzyna Kulczycka

Izabela Gutowska

Affiliations

Soon will be listed here.

Abstract

Recent studies on cyclin-dependent kinase (CDK) inhibitors have revealed that small molecule drugs have become very attractive for the treatment of cancer and neurodegenerative disorders. Most CDK inhibitors have been developed to target the ATP binding pocket. However, CDK kinases possess a very similar catalytic domain and three-dimensional structure. These features make it difficult to achieve required selectivity. Therefore, inhibitors which bind outside the ATP binding site present a great interest in the biomedical field, both from the fundamental point of view and for the wide range of their potential applications. This review tries to explain whether the ATP competitive inhibitors are still an option for future research, and highlights alternative approaches to discover more selective and potent small molecule inhibitors.

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References

Stevens A, Maupin M . 5,6-Dichloro-1-beta-D-ribofuranosylbenzimidazole inhibits a HeLa protein kinase that phosphorylates an RNA polymerase II-derived peptide. Biochem Biophys Res Commun. 1989; 159(2):508-15. DOI: 10.1016/0006-291x(89)90022-3. View

Simone M, Erba E, Damia G, Vikhanskaya F, Di Francesco A, Riccardi R . Variolin B and its derivate deoxy-variolin B: new marine natural compounds with cyclin-dependent kinase inhibitor activity. Eur J Cancer. 2005; 41(15):2366-77. DOI: 10.1016/j.ejca.2005.05.015. View

Parang K, Till J, Ablooglu A, Kohanski R, Hubbard S, Cole P . Mechanism-based design of a protein kinase inhibitor. Nat Struct Biol. 2001; 8(1):37-41. DOI: 10.1038/83028. View

Bergeron P, Koehler M, Blackwood E, Bowman K, Clark K, Firestein R . Design and Development of a Series of Potent and Selective Type II Inhibitors of CDK8. ACS Med Chem Lett. 2016; 7(6):595-600. PMC: 4904263. DOI: 10.1021/acsmedchemlett.6b00044. View

Atwell S, Adams J, Badger J, Buchanan M, Feil I, Froning K . A novel mode of Gleevec binding is revealed by the structure of spleen tyrosine kinase. J Biol Chem. 2004; 279(53):55827-32. DOI: 10.1074/jbc.M409792200. View

Vijayan R, He P, Modi V, Duong-Ly K, Ma H, Peterson J . Conformational analysis of the DFG-out kinase motif and biochemical profiling of structurally validated type II inhibitors. J Med Chem. 2014; 58(1):466-79. PMC: 4326797. DOI: 10.1021/jm501603h. View

Martin M, Endicott J, Noble M . Structure-based discovery of cyclin-dependent protein kinase inhibitors. Essays Biochem. 2017; 61(5):439-452. PMC: 6248306. DOI: 10.1042/EBC20170040. View

Pippin J, Qu Q, Meijer L, Shankland S . Direct in vivo inhibition of the nuclear cell cycle cascade in experimental mesangial proliferative glomerulonephritis with Roscovitine, a novel cyclin-dependent kinase antagonist. J Clin Invest. 1997; 100(10):2512-20. PMC: 508451. DOI: 10.1172/JCI119793. View

Wilhelm S, Adnane L, Newell P, Villanueva A, Llovet J, Lynch M . Preclinical overview of sorafenib, a multikinase inhibitor that targets both Raf and VEGF and PDGF receptor tyrosine kinase signaling. Mol Cancer Ther. 2008; 7(10):3129-40. DOI: 10.1158/1535-7163.MCT-08-0013. View

10.

Mousseau G, Mediouni S, Valente S . Targeting HIV transcription: the quest for a functional cure. Curr Top Microbiol Immunol. 2015; 389:121-45. PMC: 4409574. DOI: 10.1007/82_2015_435. View

11.

Bharate S, Yadav R, Battula S, Vishwakarma R . Meridianins: marine-derived potent kinase inhibitors. Mini Rev Med Chem. 2012; 12(7):618-31. DOI: 10.2174/138955712800626728. View

12.

MacCallum D, Melville J, Frame S, Watt K, Anderson S, Gianella-Borradori A . Seliciclib (CYC202, R-Roscovitine) induces cell death in multiple myeloma cells by inhibition of RNA polymerase II-dependent transcription and down-regulation of Mcl-1. Cancer Res. 2005; 65(12):5399-407. DOI: 10.1158/0008-5472.CAN-05-0233. View

13.

Sonawane Y, Taylor M, Napoleon J, Rana S, Contreras J, Natarajan A . Cyclin Dependent Kinase 9 Inhibitors for Cancer Therapy. J Med Chem. 2016; 59(19):8667-8684. PMC: 5636177. DOI: 10.1021/acs.jmedchem.6b00150. View

14.

Osborne C, Wakeling A, Nicholson R . Fulvestrant: an oestrogen receptor antagonist with a novel mechanism of action. Br J Cancer. 2004; 90 Suppl 1:S2-6. PMC: 2750773. DOI: 10.1038/sj.bjc.6601629. View

15.

Deng Y, Shipps Jr G, Zhao L, Siddiqui M, Popovici-Muller J, Curran P . Modulating the interaction between CDK2 and cyclin A with a quinoline-based inhibitor. Bioorg Med Chem Lett. 2013; 24(1):199-203. DOI: 10.1016/j.bmcl.2013.11.041. View

16.

Zhang T, Kwiatkowski N, Olson C, Dixon-Clarke S, Abraham B, Greifenberg A . Covalent targeting of remote cysteine residues to develop CDK12 and CDK13 inhibitors. Nat Chem Biol. 2016; 12(10):876-84. PMC: 5033074. DOI: 10.1038/nchembio.2166. View

17.

Su S, Yang Z, Gao H, Yang H, Zhu S, An Z . Potent and Preferential Degradation of CDK6 via Proteolysis Targeting Chimera Degraders. J Med Chem. 2019; 62(16):7575-7582. PMC: 6790125. DOI: 10.1021/acs.jmedchem.9b00871. View

18.

Montagnoli A, Valsasina B, Croci V, Menichincheri M, Rainoldi S, Marchesi V . A Cdc7 kinase inhibitor restricts initiation of DNA replication and has antitumor activity. Nat Chem Biol. 2008; 4(6):357-65. DOI: 10.1038/nchembio.90. View

19.

Wu S, McNae I, Kontopidis G, McClue S, McInnes C, Stewart K . Discovery of a novel family of CDK inhibitors with the program LIDAEUS: structural basis for ligand-induced disordering of the activation loop. Structure. 2003; 11(4):399-410. DOI: 10.1016/s0969-2126(03)00060-1. View

20.

Wu P, Clausen M, Nielsen T . Allosteric small-molecule kinase inhibitors. Pharmacol Ther. 2015; 156:59-68. DOI: 10.1016/j.pharmthera.2015.10.002. View