LCK-targeting molecular glues overcome resistance to inhibitor-based therapy in T-cell acute lymphoblastic leukemia

Drug resistance is a major challenge in Cancer therapy, especially in the context of kinase inhibitors. While targeted protein degradation (TPD) was a distinct mode of action compared to inhibition-based therapeutic targeting, the potential value of TPD in drug-resistant Cancer remains unclear. Here, we report the discovery of cereblon-recruiting molecular glue degraders (MGDs) targeting Lck, an oncogenic kinase in T-cell acute lymphoblastic leukemia (T-ALL). By high-throughput screening and medicinal chemistry optimization, we developed a series of MGDs that induced CRBN-dependent degradation of Lck as well as potent cytotoxicity in T-ALL in vitro. Structure-activity relationship analysis and ternary complex modeling revealed a non-canonical degron at the LCK-CRBN interface involving the G-loop, whose mutation disrupts this interaction. Unlike inhibitors and inhibitor-based PROTACs, these MGDs engage Lck in regions distal to the ATP binding site and thus their activities in T-ALL are not affected by gate-keeper Lck mutations that drive resistance to inhibitor-based therapeutics. Taken together, our data underscore the potential of LCK-targeting MGDs as a strategy to overcome kinase inhibitor resistance in T-ALL, highlighting a potentially generalizable strategy in Cancer therapy.