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

• Published in: ACS medicinal chemistry letters Vol. 7; no. 9; pp. 862 - 867
• Main Authors: Evans, Catherine A, Liu, Tao, Lescarbeau, André, Nair, Somarajan J, Grenier, Louis, Pradeilles, Johan A, Glenadel, Quentin, Tibbitts, Thomas, Rowley, Ann M, DiNitto, Jonathan P, Brophy, Erin E, O’Hearn, Erin L, Ali, Janid A, Winkler, David G, Goldstein, Stanley I, O’Hearn, Patrick, Martin, Christian M, Hoyt, Jennifer G, Soglia, John R, Cheung, Culver, Pink, Melissa M, Proctor, Jennifer L, Palombella, Vito J, Tremblay, Martin R, Castro, Alfredo C
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 08.09.2016; Amer Chemical Soc
• Subjects: Chemistry, Medicinal; Letter; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Science & Technology; phosphoinositide-3-kinase; neutrophil migration; immuno-oncology; IPI-549; isoform selectivity; PI3K-gamma inhibitor; INFLAMMATORY DISEASES; 3-KINASE GAMMA; P110-DELTA; RESPONSES; POTENT; AUTOIMMUNE; PI3K-DELTA; PI3K; PATHWAY; PI3K-GAMMA
• ISSN: 1948-5875; 1948-5875
• DOI: 10.1021/acsmedchemlett.6b00238

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.