2. Academic Validation
  3. Discovery, Optimization, and Evaluation of Potent and Highly Selective PI3Kγ-PI3Kδ Dual Inhibitors

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

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.

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