Characterization of a Long Acting Smooth Muscle Myosin Inhibitor, CK‐2125927, as a Novel Therapeutic Mechanism for Bronchodilation

• DOI: 10.1096/fasebj.25.1_supplement.1020.6
• Publication Date: 2021-06-21T16:05:47Z
• Authors: Malar Pannirselvam; Zhiheng Jia; Nickie Durham; Marianna Zavodovs...; David Lenzi; Sheila Clancy; James J Hartman; David J Morgans; Bradley P Morgan; Xiangping Qian; Fady I Malik
• Keywords: Bronchodilation; Methacholine; Muscle relaxation

Smooth muscle myosin is a mechanochemical enzyme that hydrolyzes ATP to generate mechanical force; ultimately all signaling pathways modulate smooth tone converge on the regulation of this motor protein. We previously showed novel inhibitor, CK‐2019165, inhibited methacholine‐induced bronchoconstriction in rat models with short duration action (~ 2 hours). Here we describe discovery and characterization long acting inhibitor for bronchodilation. Using high throughput screening, identified subsequently optimized class selective inhibitors myosin. These compounds potently inhibit ATPase (IC 50 ≤ 30 nM). An member series, CK‐2125927,, calcium‐induced contraction skinned tail artery concentration dependent manner an IC ~ 1 μM. CK‐2125927 induced concentration‐dependent relaxation methacholine‐pre‐constricted tracheal rings EC Further, (10 μM) completely electrical field stimulation‐induced constriction guinea pig 50% recovery time > 6 hours, comparable long‐acting beta‐adrenergic agonist salmeterol. Together these data suggest may provide therapeutic approach treatment diseases where plays role, such as asthma COPD.