title: A novel pyrazolo[1,5-a]pyrimidine is a potent inhibitor of cyclin-dependent protein kinases 1, 2, and 9, which demonstrates antitumor effects in human tumor xenografts following oral administration.
abstract: Cyclin-dependent protein kinases (CDKs) are central to the appropriate regulation of cell proliferation, apoptosis, and gene expression. Abnormalities in CDK activity and regulation are common features of cancer, making CDK family members attractive targets for the development of anticancer drugs. Here, we report the identification of a pyrazolo[1,5-a]pyrimidine derived compound, 4k (BS-194), as a selective and potent CDK inhibitor, which inhibits CDK2, CDK1, CDK5, CDK7, and CDK9 (IC₅₀= 3, 30, 30, 250, and 90 nmol/L, respectively). Cell-based studies showed inhibition of the phosphorylation of CDK substrates, Rb and the RNA polymerase II C-terminal domain, down-regulation of cyclins A, E, and D1, and cell cycle block in the S and G₂/M phases. Consistent with these findings, 4k demonstrated potent antiproliferative activity in 60 cancer cell lines tested (mean GI₅₀= 280 nmol/L). Pharmacokinetic studies showed that 4k is orally bioavailable, with an elimination half-life of 178 min following oral dosing in mice. When administered at a concentration of 25 mg/kg orally, 4k inhibited human tumor xenografts and suppressed CDK substrate phosphorylation. These findings identify 4k as a novel, potent CDK selective inhibitor with potential for oral delivery in cancer patients.
authors.affiliation: Dept of Oncology, Imperial College London, Hammersmith Hospital Campus, London W12 0NN, England.
authors.forename: Dean A
authors.initials: DA
authors.lastname: Heathcote
authors.forename: Hetal
authors.initials: H
authors.lastname: Patel
authors.forename: Sebastian H B
authors.initials: SH
authors.lastname: Kroll
authors.forename: Pascale
authors.initials: P
authors.lastname: Hazel
authors.forename: Manikandan
authors.initials: M
authors.lastname: Periyasamy
authors.forename: Mary
authors.initials: M
authors.lastname: Alikian
authors.forename: Seshu K
authors.initials: SK
authors.lastname: Kanneganti
authors.forename: Ashutosh S
authors.initials: AS
authors.lastname: Jogalekar
authors.forename: Bodo
authors.initials: B
authors.lastname: Scheiper
authors.forename: Marion
authors.initials: M
authors.lastname: Barbazanges
authors.forename: Andreas
authors.initials: A
authors.lastname: Blum
authors.forename: Jan
authors.initials: J
authors.lastname: Brackow
authors.forename: Alekasandra
authors.initials: A
authors.lastname: Siwicka
authors.forename: Robert D M
authors.initials: RD
authors.lastname: Pace
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Fuchter
authors.forename: James P
authors.initials: JP
authors.lastname: Snyder
authors.forename: Dennis C
authors.initials: DC
authors.lastname: Liotta
authors.forename: Paul S
authors.initials: PS
authors.lastname: Freemont
authors.forename: Eric O
authors.initials: EO
authors.lastname: Aboagye
authors.forename: R Charles
authors.initials: RC
authors.lastname: Coombes
authors.forename: Anthony G M
authors.initials: AG
authors.lastname: Barrett
authors.forename: Simak
authors.initials: S
authors.lastname: Ali
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001682:Biological Availability; D001798:Blood Proteins / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors*; D042863:Cyclin-Dependent Kinase 9 / Q000037:antagonists & inhibitors*; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008819:Mice, Nude; D008862:Microsomes, Liver / Q000378:metabolism; D008958:Models, Molecular; D010766:Phosphorylation; D011485:Protein Binding; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays
chemical_list: C555217:3-(7-(benzylamino)-3-isopropylpyrazolo(1,5-a)pyrimidin-5-ylamino)-1,2,4-butanetriol; D000970:Antineoplastic Agents; D001798:Blood Proteins; D011720:Pyrazoles; D011743:Pyrimidines; D051357:Cyclin-Dependent Kinase 2; D042863:Cyclin-Dependent Kinase 9