1. FAK-targeting PROTAC demonstrates enhanced antitumor activity against KRAS mutant non-small cell lung cancer
Jinyuan Liu, Lei Xue, Xiang Xu, Jinhua Luo, Shijiang Zhang Exp Cell Res. 2021 Nov 15;408(2):112868.doi: 10.1016/j.yexcr.2021.112868.Epub 2021 Oct 12.
Focal adhesion kinase (FAK) has been established as a promising therapeutic target for KRAS mutant non-small cell lung cancer (NSCLC). However, phase II clinical trials of a FAK inhibitor (Defactinib) have only shown modest antitumor activity. To address this challenge, here we report the use of a FAK-targeting proteolysis targeting chimera (D-PROTAC) to treat KRAS mutant NSCLC. We validated that D-PROTAC could efficiently eliminate FAK protein via the ubiquitin-proteasome pathway in KRAS mutant NSCLC A427 cells, causing over 90% degradation at 800 nM. After comparing both in vitro and in vivo therapeutic efficacies, we demonstrated that D-PRTOAC outperformed Defactinib in inhibiting tumor growth. Specifically, D-PROTAC at 800 nM reduced cell viability, migration, and invasion by ~80%. Furthermore, a ~85% suppression of tumor growth was elicited by D-PROTAC when intratumorally administrated at 10 mg/kg in subcutaneous A427-bearing mice. These results thus demonstrate for the first time that PROTACs may serve as promising therapeutic agents for the intractable NSCLC harboring KRAS mutations.
2. FAK inhibitors as promising anticancer targets: present and future directions
Muhamad Mustafa, Amer Ali Abd El-Hafeez, Dalia A Abdelhafeez, Dalia Abdelhamid, Yaser A Mostafa, Pradipta Ghosh, Alaa M Hayallah0, Gamal El-Din A Abuo-Rahma Future Med Chem. 2021 Sep;13(18):1559-1590.doi: 10.4155/fmc-2021-0015.Epub 2021 Aug 3.
FAK, a nonreceptor tyrosine kinase, has been recognized as a novel target class for the development of targeted anticancer agents. Overexpression of FAK is a common occurrence in several solid tumors, in which the kinase has been implicated in promoting metastases. Consequently, designing and developing potent FAK inhibitors is becoming an attractive goal, and FAK inhibitors are being recognized as a promising tool in our armamentarium for treating diverse cancers. This review comprehensively summarizes the different classes of synthetically derived compounds that have been reported as potent FAK inhibitors in the last three decades. Finally, the future of FAK-targeting smart drugs that are designed to slow down the emergence of drug resistance is discussed.
3. Addressing Kinase-Independent Functions of Fak via PROTAC-Mediated Degradation
Philipp M Cromm, Kusal T G Samarasinghe, John Hines, Craig M Crews J Am Chem Soc. 2018 Dec 12;140(49):17019-17026.doi: 10.1021/jacs.8b08008.Epub 2018 Nov 28.
Enzymatic inhibition has proven to be a successful modality for the development of many small-molecule drugs. In recent years, small-molecule-induced protein degradation has emerged as an orthogonal therapeutic strategy that has the potential to expand the druggable target space. Focal adhesion kinase (Fak) is a key player in tumor invasion and metastasis, acting simultaneously as a kinase and a scaffold for several signaling proteins. While previous efforts to modulate Fak activity were limited to kinase inhibitors with low success in clinical studies, protein degradation offers a possibility to simultaneously block Fak's kinase signaling and scaffolding capabilities. Here, we report the development of a selective and potent Fak degrader, PROTAC-3, which outperforms a clinical candidate, defactinib, with respect to Fak activation as well as Fak-mediated cell migration and invasion. These results underline the potential that PROTACs offer in expanding the druggable space and controlling protein functions that are not easily addressed by traditional small-molecule therapeutics.
