Discovery of pyrazolo[1,5-a]pyridines as p110α-selective PI3 kinase inhibitors

Kendall, Jackie; O'Connor, PD; Marshall, Andrew; Frédérick, R; Marshall, ES; Lill, CL; Lee, Woo Jeong; Kolekar, S; Chao, M; Malik, Alisha; Yu, S; Chaussade, C; Buchanan, Christina; Rewcastle, Gordon; Baguley, Bruce; Flanagan, Jack; Jamieson, Stephen; Denny, William; Shepherd, Peter

Discovery of pyrazolo[1,5-a]pyridines as p110α-selective PI3 kinase inhibitors

Kendall, Jackie ; O'Connor, PD ; Marshall, Andrew ; Frédérick, R ; Marshall, ES ; Lill, CL ; Lee, Woo Jeong ; Kolekar, S ; Chao, M ; Malik, Alisha ; Yu, S ; Chaussade, C ; Buchanan, Christina ; Rewcastle, Gordon ; Baguley, Bruce ; Flanagan, Jack ; Jamieson, Stephen ; Denny, William ; Shepherd, Peter

Identifier: http://hdl.handle.net/2292/12008

Issue Date: 2012-01

Reference: Bioorganic and Medicinal Chemistry 20(1):69-85 2012

Rights: Copyright: Elsevier

Rights (URI): https://researchspace.auckland.ac.nz/docs/uoa-docs/rights.htm

Abstract:

We have made a novel series of pyrazolo[1,5-a]pyridines as PI3 kinase inhibitors, and demonstrated their selectivity for the p110α isoform over the other Class Ia PI3 kinases. We investigated the SAR around the pyrazolo[1,5-a]pyridine ring system, and found compound 5x to be a particularly potent example (p110α IC50 0.9 nM). This compound inhibits cell proliferation and phosphorylation of Akt/PKB, a downstream marker of PI3 kinase activity, and showed in vivo activity in an HCT-116 human xenograft model.

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