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LCK-targeting molecular glues overcome resistance to inhibitor-based therapy in T-cell acute lymphoblastic leukemia
Abstract:
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.
Insights
New molecular glues targeting LCK kinase offer a promising strategy against T-cell acute lymphoblastic leukemia (T-ALL). These degraders overcome drug resistance by engaging LCK differently than traditional inhibitors.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Drug resistance to kinase inhibitors is a significant hurdle in cancer therapy.
- Targeted protein degradation (TPD) presents an alternative therapeutic modality, but its efficacy in resistant cancers is not fully understood.
Purpose of the Study:
- To investigate the potential of TPD using cereblon-recruiting molecular glue degraders (MGDs) against drug-resistant T-cell acute lymphoblastic leukemia (T-ALL).
- To discover and optimize MGDs targeting the oncogenic kinase LCK in T-ALL.
Main Methods:
- High-throughput screening and medicinal chemistry optimization were employed to develop novel MGDs.
- Structure-activity relationship analysis and ternary complex modeling elucidated the interaction interface between LCK and CRBN.
- In vitro cytotoxicity assays were performed on T-ALL cell lines.
Main Results:
- Novel MGDs were developed that induce CRBN-dependent LCK degradation and potent cytotoxicity in T-ALL.
- A non-canonical degron involving the LCK G-loop was identified, crucial for the MGD-CRBN interaction.
- These MGDs target LCK at regions distinct from the ATP-binding site, evading resistance mechanisms like gatekeeper mutations.
Conclusions:
- LCK-targeting MGDs demonstrate potential as a strategy to overcome kinase inhibitor resistance in T-ALL.
- This approach highlights a potentially generalizable TPD strategy for treating resistant cancers.
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