A design approach for bitopic kinase inhibitors.
- Open access
Bitopic kinase inhibitors designed with optimized parameters can surpass existing drugs like ponatinib in potency and safety, especially against resistant ABL1 mutants.
- Why it matters: Overcoming resistance mutations and off-target effects in kinase inhibitors is critical for improving cancer treatments, but current drugs often face toxicity and limited efficacy.
- What they did: Using ABL1 and EGFR as models, the study systematically explored ligand choice, linkage vector, and linker length to enhance potency through inter-ligand cooperativity and linker entropy, leading to the design of PonatiLink-2.
- The result: PonatiLink-2 maintains or exceeds ponatinib’s potency against resistant mutants, offers a wider therapeutic window, and outperforms existing treatments in mouse models, enabling safer, more effective therapies.