4BCP

Structure of CDK2 in complex with cyclin A and a 2-amino-4-heteroaryl- pyrimidine inhibitor

Summary for 4BCP

• Entry DOI: 10.2210/pdb4bcp/pdb
• Related: 4BCF 4BCG 4BCH 4BCI 4BCJ 4BCK 4BCM 4BCN 4BCO 4BCQ
• Descriptor: CYCLIN-DEPENDENT KINASE 2, CYCLIN-A2, 2-[[3-(1,4-diazepan-1-yl)phenyl]amino]-4-[4-methyl-2-(methylamino)-1,3-thiazol-5-yl]pyrimidine-5-carbonitrile, ... (6 entities in total)
• Functional Keywords: transferase-cell cycle complex, cdk-cyclin complex, cyclin-inhibitor, structure-based drug design, transferase/cell cycle
• Biological source: HOMO SAPIENS (HUMAN); More
• Cellular location: Cytoplasm, cytoskeleton, microtubule organizing center, centrosome: P24941; Nucleus: P20248
• Total number of polymer chains: 4
• Total formula weight: 129866.31

Authors

Hole, A.J.,Baumli, S.,Wang, S.,Endicott, J.A.,Noble, M.E.M. (deposition date: 2012-10-02, release date: 2013-04-17, Last modification date: 2024-11-13)

Primary citation

Shao, H.,Shi, S.,Huang, S.,Hole, A.,Abbas, A.Y.,Baumli, S.,Liu, X.,Lam, F.,Foley, D.W.,Fischer, P.M.,Noble, M.,Endicott, J.A.,Pepper, C.,Wang, S.
Substituted 4-(Thiazol-5-Yl)-2-(Phenylamino)Pyrimidines are Highly Active Cdk9 Inhibitors: Synthesis, X-Ray Crystal Structure, Sar and Anti-Cancer Activities.
J.Med.Chem., 56:640-, 2013

PubMed Abstract: Cancer cells often have a high demand for antiapoptotic proteins in order to resist programmed cell death. CDK9 inhibition selectively targets survival proteins and reinstates apoptosis in cancer cells. We designed a series of 4-thiazol-2-anilinopyrimidine derivatives with functional groups attached to the C5-position of the pyrimidine or to the C4-thiazol moiety and investigated their effects on CDK9 potency and selectivity. One of the most selective compounds, 12u inhibits CDK9 with IC(50) = 7 nM and shows over 80-fold selectivity for CDK9 versus CDK2. X-ray crystal structures of 12u bound to CDK9 and CDK2 provide insights into the binding modes. This work, together with crystal structures of selected inhibitors in complex with both enzymes described in a companion paper, (34) provides a rationale for the observed SAR. 12u demonstrates potent anticancer activity against primary chronic lymphocytic leukemia cells with a therapeutic window 31- and 107-fold over those of normal B- and T-cells.

PubMed: 23301767
DOI: 10.1021/JM301475F

Experimental method

X-RAY DIFFRACTION (2.26 Å)