3rwp

Publication Abstract from PubMed

Analogs substituted with various amines at the 6-position of the pyrazine ring on (4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-pyrazin-2-yl-methano ne were discovered as potent and selective inhibitors of PDK1 with potential as anti-cancer agents. An early lead with 2-pyridine-3-yl-ethylamine as the pyrazine substituent showed moderate potency and selectivity. Structure-based drug design led to improved potency and selectivity against PI3Kalpha through a combination of cyclizing the ethylene spacer into a saturated, five-membered ring and by substitution on the 4-position of the aryl ring with a fluorine. ADME properties were improved by lowering the lipophilicity with heteroatom replacements in the saturated, five-membered ring. The optimized analogs have a PDK1 Ki of 1 nM and >100-fold selectivity against PI3K/AKT-pathway kinases. The cellular potency of these analogs was assessed by the inhibition of AKT phosphorylation (T308) and by their anti-proliferation activity against a number of tumor cell lines.

Discovery of Novel, Potent and Selective Inhibitors of 3-Phosphoinositide-Dependent Kinase (PDK1).,Murphy ST, Bailey S, Burke BJ, Chappie TA, Ferre R, Greasley S, Hickey MJ, Humphrey J, Kablaoui N, Kath J, Kazmirski S, Kraus M, Kupchinskey S, Li J, Marx MA, Richter D, Tanis SP, Tran K, Vernier W, Alton G, Baxi SM, Ermolieff J, Lingardo L, Xie Z, Yin MJ, Yu XH J Med Chem. 2011 Oct 31. PMID:22040023^[1]

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