Development of Clinically Viable Non-Muscle Myosin II Small Molecule Inhibitors with Broad Therapeutic Potential
Résumé
Research suggests numerous indications, from axon regeneration and cancer, would benefit from a small molecule inhibitor of non-muscle myosin II, a molecular motor that regulates the actin cytoskeleton.
• Current chemical probe options are very limited and lack sufficient safety for in vivo studies, which we show is primarily due to potent inhibition of cardiac myosin II. • Rational design that focused on improving target selectivity over the pan-myosin II inhibitor, blebbistatin, led to the identification of MT-228, a small molecule inhibitor with a wide therapeutic window. • High-resolution structure of MT-228 bound to myosin II reveals that selectivity results from a different positioning compared to blebbistatin and an important sequence difference between cardiac and non-muscle myosin II in the inhibitor binding pocket. • A single administration of MT-228 shows long-lasting efficacy in animal models of stimulant use disorder, a current unmet and rapidly escalating need with no FDAapproved treatments.
Mots clés
- molecular motor
- high resolution protein-inhibitor structure
- substance use disorder
- therapeutic
- cardiac myosin II
- medicinal chemistry
- blebbistatin
- Non-muscle myosin II
- Non-muscle myosin II blebbistatin medicinal chemistry cardiac myosin II therapeutic substance use disorder cancer high resolution protein-inhibitor structure molecular motor
- cancer
- small molecule inhibitor
- synergy
- oncogenic kinases
- non-muscle myosin II
- non-muscle myosin II oncogenic kinases synergy small molecule inhibitor cancer
Domaines
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