Discovery of Orally Bioavailable Ligand Efficient Quinazolindiones as Potent and Selective Tankyrases Inhibitors

  • ACS Med Chem Lett. 2021 May 13;12(6):1005-1010. doi: 10.1021/acsmedchemlett.1c00160.
Donghui Qin  1 ,  Xiaojuan Lin  2 ,  Zhi Liu  2 ,  Yan Chen  2 ,  Zhiliu Zhang  2 ,  Chengde Wu  2 ,  Linlin Liu  2 ,  Yan Pan  2 ,  Sylvie Laquerre  1 ,  John Emery  1 ,  Jeff Fergusson  1 ,  Kimberly Roland  1 ,  Rick Keenan  1 ,  Allen Oliff  1 ,  Sanjay Kumar  1 ,  Mui Cheung  1 ,  Dai-Shi Su  1
Affiliations
  • 1. Virtual PoC DPU, Alternative Discovery and Development, IVIVT, Platform Technologies and Sciences, GlaxoSmithKline, 709 Swedeland Road, King of Prussia, Pennsylvania 19406, United States.
  • 2. WuXi AppTec, 288 Fute Zhong Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China.
PMID: 34141085 DOI: 10.1021/acsmedchemlett.1c00160
Abstract

We report herein the discovery of quinazolindiones as potent and selective tankyrase inhibitors. Elucidation of the structure-activity relationship of the lead compound 1g led to truncated analogues that have good potency in cells, pharmacokinetic (PK) properties, and excellent selectivity. Compound 21 exhibited excellent potencies in cells and proliferation studies, good selectivity, in vitro activities, and an excellent PK profile. Compound 21 also inhibited H292 xenograft tumor growth in nude mice. The synthesis, biological, pharmacokinetic, in vivo efficacy studies, and safety profiles of compounds are presented.

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