Discovery of highly potent and selective CRBN-recruiting EGFRL858R/T790M degraders in vivo

Currently, epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are widely used in the treatment of non-small cell lung cancer (NSCLC). However, the inevitable drug resistance and side effects are the current main obstacle, which motivating novel therapies. Proteolysis targeting chimera (PROTAC), a lately-developed technology to target proteins for degradation, has been utilized for drug development. Therefore, we designed, synthesized and evaluated a series of CRBN-recruiting EGFR degraders. Among them, 13a and 13b significantly inhibited NCI–H1975 cells proliferation with IC50 values of 58.08 nM and 46.82 nM, respectively, whereas exhibited more than 100 μM against A549 or H1299 cells, whose selectivity was more than 1700-fold. 13a and 13b potently induced the EGFRL858R/T790M degradation by ubiquitin proteasome system in a time- and dose-dependent manner but not that of EGFRWT, and the DC50 values of 13b was 13.2 nM, which was the most potent compound in current known CRBN-recruiting EGFRL858R/T790M degraders. 13a and 13b dramatically induced cell apoptosis, cell cycle arrest and inhibited downstream signaling pathways. Furthermore, 13a and 13b effectively and selectively inhibited NCI–H1975 xenograft tumor growth with good pharmacokinetics (PK) properties in vivo. These findings demonstrate that 13a and 13b could serve as candidates for developing the drug for treating NSCLC. [Display omitted] •13b exhibited highly inhibitory activity and selectivity (H1299 vs. NCI–H1975) more than 1700-fold.•The DC50 of 13b was 13.2 nM, which was the most potent molecular in current CRBN-recruiting EGFRL858R/T790M degrader.•13a and 13b showed dual function namely inhibition and degradation effects.•The tumor growth inhibition (TGI%) value of 13b was 63.7% on NCI–H1975 xenograft tumor model.