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

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-ylethylami...

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Bibliographic Details
Published in:	Journal of medicinal chemistry 2011-12, Vol.54 (24), p.8490-8500
Main Authors:	Murphy, Sean T, Alton, Gordon, Bailey, Simon, Baxi, Sangita M, Burke, Benjamin J, Chappie, Thomas A, Ermolieff, Jacques, Ferre, RoseAnn, Greasley, Samantha, Hickey, Michael, Humphrey, John, Kablaoui, Natasha, Kath, John, Kazmirski, Steven, Kraus, Michelle, Kupchinsky, Stan, Li, John, Lingardo, Laura, Marx, Matthew A, Richter, Dan, Tanis, Steven P, Tran, Khanh, Vernier, William, Xie, Zhi, Yin, Min-Jean, Yu, Xiao-Hong
Format:	Article
Language:	eng
Subjects:	3-Phosphoinositide-Dependent Protein Kinases Antineoplastic Agents - chemical synthesis Antineoplastic Agents - chemistry Antineoplastic Agents - pharmacology Cell Line, Tumor Crystallography, X-Ray Drug Screening Assays, Antitumor Ethylamines - chemical synthesis Ethylamines - chemistry Ethylamines - pharmacology Humans Models, Molecular Phosphorylation Protein Conformation Protein-Serine-Threonine Kinases - antagonists & inhibitors Proto-Oncogene Proteins c-akt - metabolism Pyridines - chemical synthesis Pyridines - chemistry Pyridines - pharmacology Pyrroles - chemical synthesis Pyrroles - chemistry Pyrroles - pharmacology Signal Transduction Structure-Activity Relationship
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Summary:	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 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.
ISSN:	0022-2623 1520-4804