Design, synthesis, and biological evaluation of potent FAK-degrading PROTACs

Qiaohua Qin; Ruifeng Wang; Qinglin Fu; Guoqi Zhang; Tianxiao Wu; Nian Liu; Ruicheng Lv; Wenbo Yin; Yin Sun; Yixiang Sun; Dongmei Zhao; Maosheng Cheng

doi:10.1080/14756366.2022.2100886

Journal of Enzyme Inhibition and Medicinal Chemistry (Dec 2022)

Design, synthesis, and biological evaluation of potent FAK-degrading PROTACs

Qiaohua Qin,
Ruifeng Wang,
Qinglin Fu,
Guoqi Zhang,
Tianxiao Wu,
Nian Liu,
Ruicheng Lv,
Wenbo Yin,
Yin Sun,
Yixiang Sun,
Dongmei Zhao,
Maosheng Cheng

Affiliations

Qiaohua Qin: Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, PR China
Ruifeng Wang: Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, PR China
Qinglin Fu: Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, PR China
Guoqi Zhang: Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, PR China
Tianxiao Wu: Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, PR China
Nian Liu: Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, PR China
Ruicheng Lv: Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, PR China
Wenbo Yin: Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, PR China
Yin Sun: Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, PR China
Yixiang Sun: Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, PR China
Dongmei Zhao: Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, PR China
Maosheng Cheng: Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang, PR China

DOI: https://doi.org/10.1080/14756366.2022.2100886
Journal volume & issue: Vol. 37, no. 1
pp. 2241 – 2255

Abstract

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FAK mediated tumour cell migration, invasion, survival, proliferation and regulation of tumour stem cells through its kinase-dependent enzymatic functions and kinase-independent scaffolding functions. At present, the development of FAK PROTACs has become one of the hotspots in current pharmaceutical research to solve above problems. Herein, we designed and synthesised a series of FAK-targeting PROTACs consisted of PF-562271 derivative 1 and Pomalidomide. All compounds showed significant in vitro FAK kinase inhibitory activity, the IC50 value of the optimised PROTAC A13 was 26.4 nM. Further, A13 exhibited optimal protein degradation (85% degradation at 10 nM). Meantime, compared with PF-562271, PROTAC A13 exhibited better antiproliferative activity and anti-invasion ability in A549 cells. More, A13 had excellent plasma stability with T1/2 >194.8 min. There are various signs that PROTAC A13 could be useful as expand tool for studying functions of FAK in biological system and as potential therapeutic agents.

Published in Journal of Enzyme Inhibition and Medicinal Chemistry

ISSN: 1475-6366 (Print); 1475-6374 (Online)
Publisher: Taylor & Francis Group
Country of publisher: United Kingdom
LCC subjects: Medicine: Therapeutics. Pharmacology
Website: https://www.tandfonline.com/journals/ienz

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