Synthesis and identification of [1,3,5]triazine-pyridine biheteroaryl as a novel series of potent cyclin-dependent kinase inhibitors.
On the basis of previous studies, we identified pyrazine-pyridine A as a potent vascular endothelial growth factor inhibitor and pyrimidine-pyridine B as a moderately potent cyclin dependent kinase (CDK) inhibitor. A proposed combination of CGP-60474 and compound B led to the discovery of [1,3,5]triazine-pyridine as a new series of potent CDK inhibitors. Palladium-catalyzed C-C bond formation reactions, particularly the Negishi coupling reaction, were used to assemble various triazine-heteroaryl analogues effectively. Among them, compound 20 displayed high inhibitory potency at CDK1 (IC(50) = 0.021 microM), CDK2, and CDK5 and submicromolar potency at CDK4, CDK6, and CDK7. Compound 20 also displayed high potency at GSK-3beta. It demonstrated potent antiproliferative activity on various tumor cell lines, including HeLa, HCT-116, U937, and A375. When 20 was administered intraperitoneally at 150 and 125 mg/kg to nude mice bearing human A375 xenografts, the compound produced a significant survival increase. Molecular docking studies were conducted in an attempt to enhance the understanding of the observed structure-activity relationship.
Drug Discovery Division, Johnson & Johnson Pharmaceutical Research and Development, L.L.C., Raritan, New Jersey 08869, USA. gkuo@prdus.jnj.com
Gee-Hong
GH
Kuo
Alan
A
Deangelis
Stuart
S
Emanuel
Aihua
A
Wang
Yan
Y
Zhang
Peter J
PJ
Connolly
Xin
X
Chen
Robert H
RH
Gruninger
Catherine
C
Rugg
Angel
A
Fuentes-Pesquera
Steven A
SA
Middleton
Linda
L
Jolliffe
William V
WV
Murray
D000631:Aminopyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008958:Models, Molecular; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013843:Thiazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014183:Transplantation, Heterologous; D014227:Triazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
C502815:3-(4-(4-(3-chlorophenylamino)-(1,3,5)triazin-2-yl)pyridin-2-ylamino)propan-1-ol; D000631:Aminopyridines; D000970:Antineoplastic Agents; D011725:Pyridines; D013843:Thiazines; D014227:Triazines; D018844:Cyclin-Dependent Kinases