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

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.

SUBMITTER: Qin D

PROVIDER: S-EPMC8201761 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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

Qin Donghui D Lin Xiaojuan X Liu Zhi Z Chen Yan Y Zhang Zhiliu Z Wu Chengde C Liu Linlin L Pan Yan Y Laquerre Sylvie S Emery John J Fergusson Jeff J Roland Kimberly K Keenan Rick R Oliff Allen A Kumar Sanjay S Cheung Mui M Su Dai-Shi DS

ACS medicinal chemistry letters 20210513 6

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 xe ...[more]

PMID: 34141085

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