Cutting-Edge FAK-targeting PROTACs: design, synthesis, and biological evaluation

doi:10.5246/jcps.2024.09.057

Journal of Chinese Pharmaceutical Sciences ›› 2024, Vol. 33 ›› Issue (9): 767-782.DOI: 10.5246/jcps.2024.09.057

• Original articles • Next Articles

Cutting-Edge FAK-targeting PROTACs: design, synthesis, and biological evaluation

Ruifeng Wang¹^,³^,⁴^,^#, Xin Zhao²^,^#, Hongbao Hou², Ke Chen¹^,⁴, Shuihua Liu¹^,⁴, Ruyue Ren¹^,⁴, Yunfeng Liu³^,^*(), Yi Zhang¹^,²^,^*()

¹ Medicinal Basic Research Innovation Center of Chronic Kidney Disease, Ministry of Education, Shanxi Medical University, Taiyuan 030001, Shanxi, China
² Department of Pharmacology, Shanxi Medical University, Taiyuan 030001, Shanxi, China
³ Department of Endocrinology, First Hospital of Shanxi Medical University, Shanxi Medical University, Taiyuan 030001, Shanxi, China
⁴ Department of Pharmacy, Shanxi Medical University, Taiyuan 030001, Shanxi, China

Received:2024-01-12 Revised:2024-02-21 Accepted:2024-04-19 Online:2024-10-03 Published:2024-10-03
Contact: Yunfeng Liu, Yi Zhang
About author:
^# Ruifeng Wang and Xin Zhao contributed equally to this work.
Supported by:
National Natural Science Foundation of China (Grant No. 82204222, 81973378 and 82073909), China Postdoctoral Science Foundation (Grant No. 2022M722012), Shanxi Province Science Foundation for Youths (Grant No. 20210302124191), Open Fund from Medicinal Basic Research Innovation Center of Chronic Kidney Disease, Ministry of Education, Shanxi Medical University (Grant No. CKD/SXMU-2024-02).

Abstract

Abstract:

Focal adhesion kinase (FAK) is an intracellular tyrosine kinase that plays a critical role in the occurrence, development, and metastasis of cancer through both its kinase-dependent catalytic functions and kinase-independent scaffolding functions. Current kinase inhibitors target only its catalytic activity, leaving the scaffolding functions unaffected. However, proteolysis targeting chimeras (PROTACs) offers a promising approach by degrading the entire FAK protein, thereby inhibiting both functions simultaneously. In this study, we designed and synthesized novel PROTAC degraders, utilizing a defactinib derivative (compound 12) as the FAK ligand and a lenalidomide analog as the E3 ligase ligand. The structures of these compounds were confirmed through ¹H NMR, ¹³C NMR, and high-resolution mass spectrometry (HRMS). Among the synthesized compounds, the optimized compound 16b exhibited potent degradation activity against FAK protein in A549 cells, with a DC₅₀ of 6.16 ± 1.13 nM, significantly inhibiting the proliferation and colony formation of these cells. Compared to defactinib, 16b showed enhanced inhibition of A549 cell migration and invasion. Furthermore, our research demonstrated that the rapid and effective FAK degradation induced by 16b was mediated by a CRBN-dependent proteasome mechanism.

Key words: FAK, PROTAC, Migration, Invasion

Supporting: /attached/file/20241006/20241006175219_831.pdf

Ruifeng Wang, Xin Zhao, Hongbao Hou, Ke Chen, Shuihua Liu, Ruyue Ren, Yunfeng Liu, Yi Zhang. Cutting-Edge FAK-targeting PROTACs: design, synthesis, and biological evaluation[J]. Journal of Chinese Pharmaceutical Sciences, 2024, 33(9): 767-782.

Figures/Tables 11

References 26

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Cutting-Edge FAK-targeting PROTACs: design, synthesis, and biological evaluation

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