Discovery of Potent and Selective PI3Kγ Inhibitors
Samuel L. Drew, Rhiannon Thomas‐Tran, Joel W. Beatty, Jeremy Fournier, Kenneth V. Lawson, Dillon H. Miles, Guillaume Mata, Ehesan U. Sharif, Xuelei Yan, Artur K. Mailyan, Elaine Ginn, Jie Chen, Kent Wong, Divyank Soni, Puja Dhanota, Pei‐Yu Chen, Stefan G. Shaqfeh, Cesar Meleza, Amber Pham, Ada Chen, Xiaoning Zhao, Jesus Banuelos, Lixia Jin, Ulrike Schindler, Matthew J. Walters, Stephen W. Young, Nigel P.C. Walker, Manmohan R. Leleti, Jay P. Powers, Jenna L. Jeffrey
Abstract
= 0.064 μM, THP-1 cells), which displays >600-fold selectivity for PI3Kγ over the other class I isoforms and is a promising step toward the identification of a clinical development candidate. The structure-activity relationships identified throughout this campaign demonstrate that greater γ-selectivity can be achieved by inhibitors that occupy an "alkyl-induced" pocket and possess bicyclic hinge-binding motifs capable of forming more than one hydrogen bond to the hinge region of PI3Kγ.