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

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Drug resistance is a significant hurdle in treating hematologic malignancies, particularly T-cell acute lymphoblastic leukemia (T-ALL).
• Kinase inhibitors have improved T-ALL treatment but are often rendered ineffective by acquired resistance.
• Targeted protein degradation (TPD) presents a novel therapeutic strategy distinct from traditional inhibition.

Purpose of the Study:

• To investigate the potential of TPD, specifically cereblon-recruiting molecular glue degraders (MGDs), in overcoming drug resistance in T-ALL.
• To discover and optimize MGDs targeting LCK, an oncogenic kinase implicated in T-ALL pathogenesis.

Main Methods:

• High-throughput screening and medicinal chemistry were employed to identify and refine LCK-targeting MGDs.
• In vitro assays were used to assess CRBN-dependent LCK degradation and cytotoxicity in T-ALL cell lines.
• Structure-activity relationship analysis and ternary complex modeling elucidated the interaction between MGDs, LCK, and CRBN.

Main Results:

• A series of potent MGDs were developed that induce CRBN-dependent LCK degradation and exhibit significant cytotoxicity in T-ALL cells.
• A novel, non-canonical degron involving the LCK G-loop was identified at the LCK-CRBN interface.
• These MGDs function independently of LCK mutations (e.g., gatekeeper mutations) that confer resistance to ATP-competitive inhibitors.

Conclusions:

• LCK-targeting MGDs represent a promising therapeutic strategy to overcome kinase inhibitor resistance in T-ALL.
• This approach offers a potential framework for targeting kinase dependencies in other drug-refractory hematologic malignancies.
• The distinct mechanism of action of MGDs, engaging LCK outside the ATP-binding site, circumvents common resistance pathways.