Design, synthesis and biological evaluation of 6-pyridylmethylaminopurines as CDK inhibitors.

Article Details

Citation

Wilson SC, Atrash B, Barlow C, Eccles S, Fischer PM, Hayes A, Kelland L, Jackson W, Jarman M, Mirza A, Moreno J, Nutley BP, Raynaud FI, Sheldrake P, Walton M, Westwood R, Whittaker S, Workman P, McDonald E

Design, synthesis and biological evaluation of 6-pyridylmethylaminopurines as CDK inhibitors.

Bioorg Med Chem. 2011 Nov 15;19(22):6949-65. doi: 10.1016/j.bmc.2011.08.051. Epub 2011 Aug 31.

PubMed ID
21982796 [ View in PubMed
]
Abstract

The cyclin-dependent kinase (CDK) inhibitor seliciclib (1, CYC202) is in phase II clinical development for the treatment of cancer. Here we describe the synthesis of novel purines with greater solubility, lower metabolic clearance, and enhanced potency versus CDKs. These compounds exhibit novel selectivity profiles versus CDK isoforms. Compound alphaSbetaR-21 inhibits CDK2/cyclin E with IC(50)=30 nM, CDK7-cyclin H with IC(50)=1.3 muM, and CDK9-cyclinT with IC(50)=0.11 muM; it (CCT68127) inhibits growth of HCT116 colon cancer cells in vitro with GI(50)=0.7 muM; and shows antitumour activity when dosed p.o. at 50mg/kg to mice bearing HCT116 solid human tumour xenografts.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
SeliciclibCyclin-dependent kinase 1IC 50 (nM)17000N/AN/ADetails
SeliciclibMitogen-activated protein kinase 1IC 50 (nM)>25000N/AN/ADetails