Design, synthesis and biological evaluation of 6-pyridylmethylaminopurines as CDK inhibitors.
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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
Drug Target Property Measurement pH Temperature (°C) Seliciclib Cyclin-dependent kinase 1 IC 50 (nM) 17000 N/A N/A Details Seliciclib Mitogen-activated protein kinase 1 IC 50 (nM) >25000 N/A N/A Details