Design and evaluation of anaplastic lymphoma kinase degraders using a covalent fumarate handle

Abstract

Targeted protein degradation has emerged as a novel therapeutic paradigm in drug discovery. Despite the FDA approval of anaplastic lymphoma kinase (ALK) inhibitors, the pursuit of compounds with enhanced potency and prolonged efficacy remains crucial to mitigate inevitable adverse effects. In this context, we endeavored to develop ALK degraders utilizing FDA-approved ALK inhibitors-crizotinib, ceritinib, brigatinib, and alectinib-as ALK binders, along with 4-methoxyphenylfumarate as a covalent handle to bind to RNF126 E3 ligase. Among the synthesized compounds, dALK-3-derived from brigatinib-efficiently induced the proteasomal degradation of EML4-ALK and exhibited a 10-fold superior anti-proliferative effect on H3122 cells compared to brigatinib. However, the enhanced anti-proliferative activity of dALK-3 was found to be independent of RNF126, a presumed potential E3 ligase, suggesting the need for investigation of other components within the ubiquitin-proteasome system. Our findings further support the potential application of the fumarate moiety as a binder for E3 ligases in targeted protein degradation.

Keywords: Anaplastic lymphoma kinase; Brigatinib; Molecular glue degrader; RNF126 E3 ligase; Targeted protein degradation.