2. Academic Validation
  3. Fragment-based structure-activity relationship analysis of CK-571 reveals non-interacting groups drive smooth muscle myosin selectivity

Fragment-based structure-activity relationship analysis of CK-571 reveals non-interacting groups drive smooth muscle myosin selectivity

  • Eur J Med Chem. 2025 Dec 16:305:118476. doi: 10.1016/j.ejmech.2025.118476.
Sharad Kumar Suthar 1,  Tamás Jernei 1,  Csilla Kurdi 2,  Ádam I Horváth 2,  Anna Ágnes Rauscher 3,  Máté Gyimesi 4,  András Málnási-Csizmadia 5
Affiliations

Affiliations

  • 1 Motorpharma Limited, Batthyány utca 54, H-1015, Budapest, Hungary; Printnet Limited, Kisgömb utca 25-27, H-1135, Budapest, Hungary.
  • 2 Motorpharma Limited, Batthyány utca 54, H-1015, Budapest, Hungary; Department of Biochemistry, Eötvös Loránd University, Pázmány Péter sétány 1/C, H-1117, Budapest, Hungary.
  • 3 Motorpharma Limited, Batthyány utca 54, H-1015, Budapest, Hungary.
  • 4 Motorpharma Limited, Batthyány utca 54, H-1015, Budapest, Hungary; Department of Biochemistry, Eötvös Loránd University, Pázmány Péter sétány 1/C, H-1117, Budapest, Hungary; Clinch Biosciences LLC, 111 Huntington Ave Suite 2500, Boston, MA 02199, United States.
  • 5 Motorpharma Limited, Batthyány utca 54, H-1015, Budapest, Hungary; Department of Biochemistry, Eötvös Loránd University, Pázmány Péter sétány 1/C, H-1117, Budapest, Hungary; Clinch Biosciences LLC, 111 Huntington Ave Suite 2500, Boston, MA 02199, United States; HUN-REN-ELTE Motor Pharmacology Research Group, Pázmány Péter sétány 1/c, H-1117, Budapest, Hungary. Electronic address: [email protected].
PMID: 41518957 DOI: 10.1016/j.ejmech.2025.118476
Abstract

Smooth muscle myosin-2 (SMM) is a promising target for treating asthma and COPD, but selective inhibition remains challenging due to the high conservation of myosin-2 isoforms. CK-571 is the first potent and selective SMM inhibitor, despite binding to an allosteric site conserved across isoforms. We performed a fragment-based structure-activity relationship analysis to deconstruct CK-571 and define the role of each segment. The isoquinoline-carbamate and chloro-fluorobenzyl moieties were found to be inactive when isolated. Surprisingly, the presence of a methyl group and a solvent-exposed pair of non-interacting dihydroxyl groups dramatically enhanced potency by up to 100-fold, despite no direct contact with the protein. These findings highlight the critical contribution of non-interacting, flexible groups in optimizing ligand potency and selectivity for conserved targets and establish a framework for the development of improved SMM-targeted therapeutics.

Keywords

Asthma and COPD; CK-571; Fragment-based SAR analysis; Myosin-2; Smooth muscle relaxation.

Figures
Products