Development of Clinically Viable Non-Muscle Myosin II Small Molecule Inhibitors with Broad Therapeutic Potential

Laszlo Radnai (1, 2) , Erica J Young (1, 2) , Carlos Kikuti (3, 4) , Madalyn Hafenbreidel , Rebecca F Stremel , Li Lin (5, 6) , Katalin Toth (7) , Paolo Pasetto , Xiaomin Jin , Aagam Patel , Michael Conlon , Sherri Briggs , Leïla Heidsieck (3) , H. Lee Sweeney , James Sellers (8) , Teresa Krieger-Burke , William H Martin (9) , Jay Sisco , Steven Young (10) , Paul Pearson , Gavin Rumbaugh (11, 1, 2) , Gian Luca Araldi , Steven K Duddy , Michael D Cameron (12, 1, 2) , Matthew Surman , Anne Houdusse (3, 4) , Patrick R Griffin (13, 1, 2) , Theodore M Kamenecka (1, 2) , Courtney A Miller (14, 1, 2)

1 Plymouth University
2 School of Biological and Marine Sciences
3 Biologie Cellulaire et Cancer
4 CNRS - Centre National de la Recherche Scientifique
5 Audencia Business School
6 Shenzhen University [Shenzhen]
7 Service Pharmacie
8 NHLBI - National Heart, Lung, and Blood Institute [Bethesda]
9 European Vaccine Initiative [Heidelberg, Germany]
10 University of Waterloo [Waterloo]
11 Department of Neuroscience
12 Department of Molecular Therapeutics
13 The Scripps Research Institute [La Jolla, San Diego]
14 New College of Florida

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.

Keywords: non-muscle myosin II oncogenic kinases synergy small molecule inhibitor cancer; non-muscle myosin II; oncogenic kinases; synergy; small molecule inhibitor; cancer; Non-muscle myosin II blebbistatin medicinal chemistry cardiac myosin II therapeutic substance use disorder cancer high resolution protein-inhibitor structure molecular motor; Non-muscle myosin II; blebbistatin; medicinal chemistry; cardiac myosin II; therapeutic; substance use disorder; high resolution protein-inhibitor structure; molecular motor

Domains: Life Sciences [q-bio]

Laszlo Radnai, Erica J Young, Carlos Kikuti, Madalyn Hafenbreidel, Rebecca F Stremel, et al.. Development of Clinically Viable Non-Muscle Myosin II Small Molecule Inhibitors with Broad Therapeutic Potential. 2024. ⟨hal-04775437⟩