Development of Clinically Viable Non-Muscle Myosin II Small Molecule Inhibitors with Broad Therapeutic Potential - l'unam - université nantes angers le mans
Preprints, Working Papers, ... Year : 2024

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

Madalyn Hafenbreidel
  • Function : Author
Rebecca F Stremel
  • Function : Author
Katalin Toth
  • Function : Author
Paolo Pasetto
  • Function : Author
Xiaomin Jin
  • Function : Author
Aagam Patel
  • Function : Author
Michael Conlon
  • Function : Author
Sherri Briggs
  • Function : Author
H. Lee Sweeney
  • Function : Author
Teresa Krieger-Burke
  • Function : Author
Jay Sisco
  • Function : Author
Paul Pearson
  • Function : Author
Gian Luca Araldi
  • Function : Author
Steven K Duddy
  • Function : Author
Matthew Surman
  • Function : Author

Abstract

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.

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Dates and versions

hal-04775437 , version 1 (10-11-2024)

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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⟩
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