Discovery of a Potent Class of PI3Kα Inhibitors with Unique Binding Mode via Encoded Library Technology (ELT)

Hongfang Yang; Patricia F Medeiros; Kaushik Raha; Patricia Elkins; Kenneth E Lind; Ruth Lehr; Nicholas D Adams; Joelle L Burgess; Stanley J Schmidt; Steven D Knight; Kurt R Auger; Michael D Schaber; G Joseph Franklin; Yun Ding; Jennifer L DeLorey; Paolo A Centrella; Sibongile Mataruse; Steven R Skinner; Matthew A Clark; John W Cuozzo; Ghotas Evindar

doi:10.1021/acsmedchemlett.5b00025

Discovery of a Potent Class of PI3Kα Inhibitors with Unique Binding Mode via Encoded Library Technology (ELT)

ACS Med Chem Lett. 2015 Mar 20;6(5):531-6. doi: 10.1021/acsmedchemlett.5b00025. eCollection 2015 May 14.

Authors

Hongfang Yang¹, Patricia F Medeiros¹, Kaushik Raha², Patricia Elkins², Kenneth E Lind¹, Ruth Lehr², Nicholas D Adams², Joelle L Burgess², Stanley J Schmidt², Steven D Knight², Kurt R Auger², Michael D Schaber², G Joseph Franklin¹, Yun Ding¹, Jennifer L DeLorey¹, Paolo A Centrella¹, Sibongile Mataruse¹, Steven R Skinner¹, Matthew A Clark¹, John W Cuozzo¹, Ghotas Evindar¹

Affiliations

¹ MDR (Molecular Discovery Research) Boston, Platform Technology and Science, GlaxoSmithKline , 830 Winter Street, Waltham, Massachusetts 02451, United States.
² Computational and Structural Chemistry, Platform Technology and Science, Biological Reagents and Assay Development, Platform Technology and Science, Oncology Research, and Screening and Compound Profiling, Platform Technology and Science, GlaxoSmithKline , 1250 South Collegeville Road, Collegeville, Pennsylvania 19426, United States.

Abstract

In the search of PI3K p110α wild type and H1047R mutant selective small molecule leads, an encoded library technology (ELT) campaign against the desired target proteins was performed which led to the discovery of a selective chemotype for PI3K isoforms from a three-cycle DNA encoded library. An X-ray crystal structure of a representative inhibitor from this chemotype demonstrated a unique binding mode in the p110α protein.

Keywords: ELT; Encoded Library technology; PI3K p110α (H1047R); PI3Kα; p110α.