Discovery, Optimization, and Evaluation of Potent and Highly Selective PI3Kγ-PI3Kδ Dual Inhibitors

  • J Med Chem. 2019 May 23;62(10):4936-4948. doi: 10.1021/acs.jmedchem.8b02014.
Hong Jia  1 ,  Guangxiu Dai  1 ,  Weiguo Su  1 ,  Kun Xiao  1 ,  Jianyang Weng  1 ,  Zhulin Zhang  1 ,  Qing Wang  1 ,  Tianhai Yuan  1 ,  Fuying Shi  1 ,  Zheng Zhang  1 ,  Wei Chen  1 ,  Yang Sai  1 ,  Jian Wang  1 ,  Xiong Li  1 ,  Yu Cai  1 ,  Jun Yu  1 ,  Ping Ren  1 ,  Jennifer Venable  2 ,  Tadimeti Rao  2 ,  James P Edwards  3 ,  Scott D Bembenek  2
Affiliations
  • 1. Hutchison MediPharma Limited , Building 4, 720 Cai Lun Road, Zhangjiang Hi-Tech Park , Shanghai 201203 , China.
  • 2. Janssen Pharmaceuticals Research & Development , 3210 Merryfield Row , San Diego , California 92121 , United States.
  • 3. Janssen Pharmaceutical Research & Development , 1400 McKean Road , Spring House , Pennsylvania 19477 , United States.
PMID: 31033293 DOI: 10.1021/acs.jmedchem.8b02014
Abstract

An electronic density model was developed and used to identify a novel pyrrolotriazinone replacement for a quinazolinone, a commonly used moiety to impart selectivity in inhibitors for PI3Kγ and PI3Kδ. Guided by molecular docking, this new specificity piece was then linked to the hinge-binding region of the inhibitor using a novel cyclic moiety. Further structure-activity relationship optimization around the hinge region led to the discovery of candidate 26, a highly potent and selective PI3Kγ-PI3Kδ dual inhibitor with favorable drug metabolism and pharmacokinetic properties in preclinical species.