We report herein the discovery of quinazolindiones as potent and selective tankyrase inhibitors. Elucidation of the structure-activity relationship of the lead compound led to truncated analogues that have good potency in cells, pharmacokinetic (PK) properties, and excellent selectivity. Compound exhibited excellent potencies in cells and proliferation studies, good selectivity, activities, and an excellent PK profile. Compound also inhibited H292 xenograft tumor growth in nude mice. The synthesis, biological, pharmacokinetic, efficacy studies, and safety profiles of compounds are presented.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8201761 | PMC |
| http://dx.doi.org/10.1021/acsmedchemlett.1c00160 | DOI Listing |
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Discovery of Orally Bioavailable Ligand Efficient Quinazolindiones as Potent and Selective Tankyrases Inhibitors.
ACS Med Chem Lett
June 2021
Virtual PoC DPU, Alternative Discovery and Development, IVIVT, Platform Technologies and Sciences, GlaxoSmithKline, 709 Swedeland Road, King of Prussia, Pennsylvania 19406, United States.
We report herein the discovery of quinazolindiones as potent and selective tankyrase inhibitors. Elucidation of the structure-activity relationship of the lead compound led to truncated analogues that have good potency in cells, pharmacokinetic (PK) properties, and excellent selectivity. Compound exhibited excellent potencies in cells and proliferation studies, good selectivity, activities, and an excellent PK profile.
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