Discovery of novel, potent, and selective inhibitors of 3-phosphoinositide-dependent kinase (PDK1)

  • J Med Chem. 2011 Dec 22;54(24):8490-500. doi: 10.1021/jm201019k.
Sean T Murphy  1 ,  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
Affiliations
  • 1. Pfizer Global Research and Development, 10770 Science Center Drive, San Diego, California 92121, United States. [email protected]
PMID: 22040023 DOI: 10.1021/jm201019k
Abstract

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 PI3Kα 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 Ki 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.

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