Discovery of the First Potent ROR1 Degrader for the Treatment of Non-Small Cell Lung Cancer

Abstract

ROR1 has been identified as a pseudokinase, functioning as an allosteric regulator in tumor progression. Aberrant overexpression of ROR1 has been observed in various malignancies, highlighting its potential as therapeutic target for cancer therapy. Modulation of ROR1 by proteolysis targeting chimera degrader instead of traditional inhibitor could offer great efficiency in blocking its kinase-independent regulatory function. Here, we report the first potent ROR1 degraders constructed by connecting the E3 ligand to a ROR1 binder. One representative compound 11d exhibited remarkable efficacy in depleting ROR1 protein with a DC₅₀ value of 40.88 nM and D_max of 93.7%. Mechanistic investigations illuminated that compound 11d triggers ROR1 protein degradation in a ubiquitin proteasome system (UPS)-dependent manner. Additionally, compound 11d displayed a significantly enhanced ability to inhibit ROR1 signaling, induce apoptosis, and suppress proliferation in lung cell lines compared to the warhead ROR1 binder. These findings underscore the substantial potential of ROR1 degrader for the treatment of non-small cell lung cancer (NSCLC) cells.