Discovery of Novel, Potent, and Selective Inhibitors of 3-Phosphoinositide-Dependent Kinase (PDK1)

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• 作者：Sean T. Murphy ; Gordon Alton ; Simon Bailey ; Sangita M. Baxi ; Benjamin J. Burke ; Thomas A. Chappie ; Jacques Ermolieff ; RoseAnn Ferre ; Samantha Greasley ; Michael Hickey ; John Humphrey ; Natasha Kablaoui ; John Kath ; Steven Kazmirski ; Michelle Kraus ; Stan Kupchinsky ; John Li ; Laura Lingardo ; Matthew A. Marx ; Dan Richter ; Steven P. Tanis ; Khanh Tran ; William Vernier ; Zhi Xie ; Min-Jean Yin ; Xiao-Hong Yu
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：December 22, 2011
• 年：2011
• 卷：54
• 期：24
• 页码：8490-8500
• 全文大小：529K
• 年卷期：v.54,no.24(December 22, 2011)
• ISSN：1520-4804

文摘

Analogues 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-ylmethanone were discovered as potent and selective inhibitors of PDK1 with potential as anticancer agents. An early lead with 2-pyridine-3-ylethylamine as the pyrazine substituent showed moderate potency and selectivity. Structure-based drug design led to improved potency and selectivity against PI3K伪 through a combination of cyclizing the ethylene spacer into a saturated, five-membered ring and substituting 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 analogues have a PDK1 K_i of 1 nM and >100-fold selectivity against PI3K/AKT-pathway kinases. The cellular potency of these analogues was assessed by the inhibition of AKT phosphorylation (T308) and by their antiproliferation activity against a number of tumor cell lines.