Discovery of a Selective Phosphoinositide-3-Kinase (PI3K)-γ Inhibitor (IPI-549) as an Immuno-Oncology Clinical Candidate

Catherine A Evans; Tao Liu; André Lescarbeau; Somarajan J Nair; Louis Grenier; Johan A Pradeilles; Quentin Glenadel; Thomas Tibbitts; Ann M Rowley; Jonathan P DiNitto; Erin E Brophy; Erin L O'Hearn; Janid A Ali; David G Winkler; Stanley I Goldstein; Patrick O'Hearn; Christian M Martin; Jennifer G Hoyt; John R Soglia; Culver Cheung; Melissa M Pink; Jennifer L Proctor; Vito J Palombella; Martin R Tremblay; Alfredo C Castro

doi:10.1021/acsmedchemlett.6b00238

Discovery of a Selective Phosphoinositide-3-Kinase (PI3K)-γ Inhibitor (IPI-549) as an Immuno-Oncology Clinical Candidate

ACS Med Chem Lett. 2016 Jul 22;7(9):862-7. doi: 10.1021/acsmedchemlett.6b00238. eCollection 2016 Sep 8.

Authors

Catherine A Evans¹, Tao Liu¹, André Lescarbeau¹, Somarajan J Nair¹, Louis Grenier¹, Johan A Pradeilles¹, Quentin Glenadel¹, Thomas Tibbitts¹, Ann M Rowley¹, Jonathan P DiNitto¹, Erin E Brophy¹, Erin L O'Hearn¹, Janid A Ali¹, David G Winkler¹, Stanley I Goldstein¹, Patrick O'Hearn¹, Christian M Martin¹, Jennifer G Hoyt¹, John R Soglia¹, Culver Cheung¹, Melissa M Pink¹, Jennifer L Proctor¹, Vito J Palombella¹, Martin R Tremblay¹, Alfredo C Castro¹

Affiliation

¹ Infinity Pharmaceuticals, Inc. , 784 Memorial Drive, Cambridge, Massachusetts 02139, United States.

Abstract

Optimization of isoquinolinone PI3K inhibitors led to the discovery of a potent inhibitor of PI3K-γ (26 or IPI-549) with >100-fold selectivity over other lipid and protein kinases. IPI-549 demonstrates favorable pharmacokinetic properties and robust inhibition of PI3K-γ mediated neutrophil migration in vivo and is currently in Phase 1 clinical evaluation in subjects with advanced solid tumors.

Keywords: IPI-549; PI3K-gamma inhibitor; immuno-oncology; isoform selectivity; neutrophil migration; phosphoinositide-3-kinase.