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 IC
50
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.