Format

Send to

Choose Destination
See comment in PubMed Commons below
J Med Chem. 2011 Dec 22;54(24):8490-500. doi: 10.1021/jm201019k. Epub 2011 Nov 23.

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

Author information

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

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.

PMID:
22040023
DOI:
10.1021/jm201019k
[Indexed for MEDLINE]
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for American Chemical Society
    Loading ...
    Support Center