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

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

Affiliation

  • 1 Pfizer Global Research and Development, 10770 Science Center Drive, San Diego, California 92121, United States. sean.murphy@takedasd.com
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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-13844
    PDK1 Inhibitor