Pyrazolo[4,3-d]pyrimidine Bioisostere of Roscovitine: Evaluation of a Novel Selective Inhibitor of Cyclin-Dependent Kinases with Antiproliferative Activity
详细信息 查看全文
- 作者：Radek Jorda ; Libor Havli虂č ; ek ; Iain W. McNae ; Malcolm D. Walkinshaw ; Jir虒í ; Voller ; Antoni虂n S虒turc ; Jana Navra虂tilova虂 ; Marek Kuzma ; Martin Mistri虂k ; Jir虒í ; Ba虂rtek ; Miroslav Strnad ; Vladimi虂r Krys虒tof
- 刊名：Journal of Medicinal Chemistry
- 出版年：2011
- 出版时间：April 28, 2011
- 年：2011
- 卷：54
- 期：8
- 页码：2980-2993
- 全文大小：1184K
- 年卷期：v.54,no.8(April 28, 2011)
- ISSN：1520-4804
文摘
Inhibition of cyclin-dependent kinases (CDKs) with small molecules has been suggested as a strategy for treatment of cancer, based on deregulation of CDKs commonly found in many types of human tumors. Here, a new potent CDK2 inhibitor with pyrazolo[4,3-d]pyrimidine scaffold has been synthesized, characterized, and evaluated in cellular and biochemical assays. 7-Benzylamino-5(R)-[2-(hydroxymethyl)propyl]amino-3-isopropyl-1(2)H-pyrazolo[4,3-d]pyrimidine, compound 7, was prepared as a bioisostere of the well-known CDK inhibitor roscovitine. An X-ray crystal structure of compound 7 bound to CDK2 has been determined, revealing a binding mode similar to that of roscovitine. Protein kinase selectivity profile of compound 7 and its biological effects (cell cycle arrest, dephosphorylation of the retinoblastoma protein, accumulation of the tumor suppressor protein p53, induction of apoptosis, inhibition of homologous recombination) are consistent with CDK inhibition as a primary mode of action. Importantly, as the anticancer activities of the pyrazolo[4,3-d]pyrimidine 7 exceed those of its bioisostere roscovitine, compound 7 reported here may be preferable for cancer therapy.