3pj8

Publication Abstract from PubMed

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-pyrazo lo[4,3-d]pyrimidine (compound 7) was prepared as a bioisostere of 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 as well as 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 anti-cancer activities of the pyrazolo[4,3-d]pyrimidine 7 exceed those of its bioisostere roscovitine, the compound 7 reported here may be preferable for cancer therapy.

Pyrazolo[4,3-d]pyrimidine Bioisostere of Roscovitine: Evaluation of a Novel Selective Inhibitor of Cyclin-dependent Kinases with Antiproliferative Activity.,Jorda R, Havlicek L, McNae IW, Walkinshaw MD, Voller J, Sturc A, Navratilova J, Kuzma M, Mistrik M, Bartek J, Strnad M, Krystof V J Med Chem. 2011 Mar 21. PMID:21417417^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.