Potent and selective inhibitors of PI3Kδ: obtaining isoform selectivity from the affinity pocket and tryptophan shelf

  • Bioorg Med Chem Lett. 2012 Jul 1;22(13):4296-302. doi: 10.1016/j.bmcl.2012.05.027.
Daniel P Sutherlin  1 ,  Stewart Baker ,  Angelina Bisconte ,  Paul M Blaney ,  Anthony Brown ,  Bryan K Chan ,  David Chantry ,  Georgette Castanedo ,  Paul DePledge ,  Paul Goldsmith ,  David M Goldstein ,  Timothy Hancox ,  Jasmit Kaur ,  David Knowles ,  Rama Kondru ,  John Lesnick ,  Matthew C Lucas ,  Cristina Lewis ,  Jeremy Murray ,  Alan J Nadin ,  Jim Nonomiya ,  Jodie Pang ,  Neil Pegg ,  Steve Price ,  Karin Reif ,  Brian S Safina ,  Laurent Salphati ,  Steven Staben ,  Eileen M Seward ,  Stephen Shuttleworth ,  Sukhjit Sohal ,  Zachary K Sweeney ,  Mark Ultsch ,  Bohdan Waszkowycz ,  Binqing Wei
Affiliations
PMID: 22672799 DOI: 10.1016/j.bmcl.2012.05.027
Abstract

A potent inhibitor of PI3Kδ that is ≥ 200 fold selective for the remaining three Class I PI3K isoforms and additional kinases is described. The hypothesis for selectivity is illustrated through structure activity relationships and crystal structures of compounds bound to a K802T mutant of PI3Kγ. Pharmacokinetic data in rats and mice support the use of 3 as a useful tool compound to use for in vivo studies.

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