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Crystallographic approach to identification of cyclin-dependent kinase 4 (CDK4)-specific inhibitors by using CDK4 mimic CDK2 protein.

Ikuta M, Kamata K, Fukasawa K, Honma T, Machida T, Hirai H, Suzuki-Takahashi I, Hayama T, Nishimura S
J Biol Chem 276 27548-54 (2001)
Related entries: 1gii, 1gij

Cited: 42 times
EuropePMC logo PMID: 11335721

Abstract

Genetic alteration of one or more components of the p16(INK4A)-CDK4,6/cyclin D-retinoblastoma pathway is found in more than half of all human cancers. Therefore, CDK4 is an attractive target for the development of a novel anticancer agent. However, it is difficult to make CDK4-specific inhibitors that do not possess activity for other kinases, especially CDK2, because the CDK family has high structural homology. The three-dimensional structure of CDK2, particularly that bound with the inhibitor, has provided useful information for the synthesis of CDK2-specific inhibitors. The same approach used to make CDK4-specific inhibitors was hindered by the failure to obtain a crystal structure of CDK4. To overcome this problem, we synthesized a CDK4 mimic CDK2 protein in which the ATP binding pocket of CDK2 was replaced with that of CDK4. This CDK4 mimic CDK2 was crystallized both in the free and inhibitor-bound form. The structural information thus obtained was found to be useful for synthesis of a CDK4-specific inhibitor that does not have substantial CDK2 activity. Namely, the data suggest that CDK4 has additional space that will accommodate a large substituent such as the CDK4 selective inhibitor. Inhibitors designed to bind into this large cavity should be selective for CDK4 without having substantial CDK2 activity. This design principle was confirmed in the x-ray crystal structure of the CDK4 mimic CDK2 with a new CDK4 selective inhibitor bound.

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Reviews citing this publication (7)

  1. Structural biology in drug design: selective protein kinase inhibitors. Scapin G. Drug Discov Today 7 601-611 (2002)
  2. Selectivity and potency of cyclin-dependent kinase inhibitors. Sridhar J, Akula N, Pattabiraman N. AAPS J 8 E204-21 (2006)
  3. Pharmacological targeting of CDK9 in cardiac hypertrophy. Krystof V, Chamrád I, Jorda R, Kohoutek J. Med Res Rev 30 646-666 (2010)
  4. Recent advances in de novo design strategy for practical lead identification. Honma T. Med Res Rev 23 606-632 (2003)
  5. Cyclin-dependent protein kinases as therapeutic drug targets for antimalarial drug development. Waters NC, Geyer JA. Expert Opin Ther Targets 7 7-17 (2003)
  6. Therapeutic potential of CDK4/6 inhibitors in renal cell carcinoma. Sager RA, Backe SJ, Ahanin E, Smith G, Nsouli I, Woodford MR, Bratslavsky G, Bourboulia D, Mollapour M. Nat Rev Urol 19 305-320 (2022)
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