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

Abstract

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 EGFR^L858R/T790M degradation by ubiquitin proteasome system in a time- and dose-dependent manner but not that of EGFR^WT, and the DC₅₀ values of 13b was 13.2 nM, which was the most potent compound in current known CRBN-recruiting EGFR^L858R/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.

Keywords: Antitumor; CADD; EGFR(L858R/T790M); PK and PD; PROTAC.