Pyrazolo[4,3-d]pyrimidine Bioisostere of Roscovitine: Evaluation of a Novel Selective Inhibitor of Cyclin-Dependent Kinases with Antiproliferative Activity

• Published in: Journal of medicinal chemistry Vol. 54; no. 8; pp. 2980 - 2993
• Main Authors: Jorda, Radek, Havlíček, Libor, McNae, Iain W, Walkinshaw, Malcolm D, Voller, Jiří, Šturc, Antonín, Navrátilová, Jana, Kuzma, Marek, Mistrík, Martin, Bártek, Jiří, Strnad, Miroslav, Kryštof, Vladimír
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 28.04.2011; Amer Chemical Soc
• Subjects: Cell Line, Tumor; Cell Proliferation - drug effects; Chemistry, Medicinal; Crystallization; Crystallography, X-Ray; Cyclin-Dependent Kinases - antagonists & inhibitors; Drug Screening Assays, Antitumor; Humans; Life Sciences & Biomedicine; Magnetic Resonance Spectroscopy; Mass Spectrometry; Models, Molecular; Pharmacology & Pharmacy; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Purines - chemistry; Purines - pharmacology; Pyrazoles - chemistry; Pyrimidines - chemistry; Recombination, Genetic; Science & Technology; Spectrophotometry, Infrared; IN-VITRO; SELICICLIB CYC202; R-ROSCOVITINE; STRUCTURE-GUIDED DESIGN; DNA-DAMAGE; DOWN-REGULATION; CELL-CYCLE; OLOMOUCINE; CANCER; PROTEIN-KINASES
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm200064p

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.