Design, synthesis, and molecular docking studies of novel pomalidomide-based PROTACs as potential anti-cancer agents targeting EGFR^WT and EGFR^T790M

Abstract

A new class of EGFR PROTACs based on pomalidomide was developed, synthesised, and tested for their cytotoxic activity against a panel of human cancer cells. Compounds 15–21 were showed to be more effective against the four tested cell lines than erlotinib. In particular, compound 16 was found to be the most potent counterpart as it was 5.55, 4.34, 5.04, and 7.18 times more active than erlotinib against MCF-7, HepG-2, HCT-116, and A549 cells, respectively. Compound 15 was revealed to be more active than doxorubicin against the four tested cell lines. Furthermore, the most potent cytotoxic compounds were studied further for their kinase inhibitory effects against EGFR^WT and EGFR^T790M using HTRF test. Compound 16 showed to be the most effective against both kinds of EGFR, with IC₅₀ values of 0.10 and 4.02 µM, respectively. Compound 16 could effectively degrade EGFR protein through ubiquitination (D_max = 96%) at 72 h in the tested cells.

Graphical Abstract

Keywords:

• EGFR
• PROTACs
• pomalidomide
• apoptosis induction
• anticancer agents

Acknowledgments

This work was partially supported by National Natural Science Foundation of China (82173759). The authors would like to thank the China Scholarship Council (CSC) for its PhD grant accorded to Moustafa Omar Aboelez Ahmed (Moustafa O. Aboelez) (2019GBJ003220), Dr. Amany Belal would like to thank Taif University Researchers Supporting Project number (T URSP-2020/35), Taif University, Taif, Saudi Arabia.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work was partially supported by National Natural Science Foundation of China [82173759], The authors would like to thank the China Scholarship Council (CSC) for its PhD grant accorded to Moustafa Omar Aboelez Ahmed (Moustafa O. Aboelez) [2019GBJ003220], and Dr. Amany Belal (Taif University Researchers Supporting Project number [TURSP-2020/35], Taif University, Taif, Saudi Arabia).