SOUTH SAN FRANCISCO, Calif., Nov. 07, 2016 (GLOBE NEWSWIRE) -- Cytokinetics, Inc. (Nasdaq:CYTK) a leader in muscle biology and the mechanics of muscle performance, today announced the publication of preclinical data characterizing a smooth muscle myosin (SMM) inhibitor that induces smooth muscle relaxation. The manuscript titled, “Highly Selective Inhibition of Myosin Motors Provides the Basis of Potential Therapeutic Application,” published in PNAS, Proceedings of the National Academy of Sciences, illustrates a mechanism of action with potential relevance for diseases of smooth muscle hypercontractility such as asthma and chronic obstructive pulmonary disease. The research was conducted in collaboration with Anne Houdusse, Institut Curie, Paris, France.
“We are continually interested in understanding the basis by which small molecule compounds modulate myosin function and characterizing the diversity of their mechanisms,” said Fady I. Malik, MD, PhD, Cytokinetics’ Executive Vice President, Research & Development. “This study is particularly interesting in that we have revealed a new mechanistic approach that may have application across a diversity of myosin inhibitors and distinguishes the binding site for these compounds from comparable compounds that may promote contractility. Importantly, the newly identified allosteric binding site on myosin has the potential to guide the design of novel class-specific myosin inhibitors.”
The objective of the study was to define the mechanism of the SMM inhibitor, CK‑2018571 (CK-571), and the structural basis that underlies its inhibition of this motor protein. The inhibitory mechanism of CK-571 was elucidated by defining the enzymatic step in which the compound traps the motor and the subsequent determination of the high-resolution structure of SMM co-crystallized with CK-571. The authors found that the compound targets an intermediate state that occurs during the myosin recovery stroke, the large conformational rearrangement that enables re-priming of the motor. Blocking this critical transition appears to result in efficient inhibition of force production. Furthermore, the atomic structure of CK-571 and the SMM complex shows that the compound binds in an allosteric pocket of the myosin motor that forms transiently during its recovery stroke - one that has not been found in previously described structures of the motor. By stabilizing an enzymatic state that can neither hydrolyze ATP nor bind actin, CK-571 prevents smooth muscle myosin from participating in mechanical force production. As the authors state, “CK-571 exemplifies an innovative and efficient mechanism to achieve complete relaxation of smooth muscle.”
Cytokinetics is a late-stage biopharmaceutical company focused on discovering, developing and commercializing first-in-class muscle activators as potential treatments for debilitating diseases in which muscle performance is compromised and/or declining. As a leader in muscle biology and the mechanics of muscle performance, the company is developing small molecule drug candidates specifically engineered to increase muscle function and contractility. Cytokinetics’ lead drug candidate is tirasemtiv, a fast skeletal muscle troponin activator, for the potential treatment of ALS. Tirasemtiv has been granted orphan drug designation and fast track status by the U.S. Food and Drug Administration and orphan medicinal product designation by the European Medicines Agency for the potential treatment of ALS. Cytokinetics retains the right to develop and commercialize tirasemtiv, subject to an option held by Astellas Pharma Inc. Cytokinetics is also collaborating with Astellas to develop CK-2127107, a fast skeletal muscle activator, for the potential treatment of spinal muscular atrophy, chronic obstructive pulmonary disease and ALS. Cytokinetics is collaborating with Amgen Inc. to develop omecamtiv mecarbil, a novel cardiac muscle activator, for the potential treatment of heart failure. Amgen holds an exclusive license worldwide to develop and commercialize omecamtiv mecarbil and Astellas holds an exclusive license worldwide to develop and commercialize CK-2127107. Both licenses are subject to Cytokinetics' specified development and commercialization participation rights. For additional information about Cytokinetics, visit http://www.cytokinetics.com/.
About Institut Curie
Institut Curie, a private, non-profit foundation, is one of the leading medical, biological and biophysical research centres in the world. Anne Houdusse is an international expert in molecular motors and small GTPases effectors, in particular as a structural biologist. A major focus of the Structural Motility Laboratory she directs is to use X-ray crystallography to solve atomic structures that help understand how myosin motors produce force and how their activity can be modulated. For additional information, visit http://bit.ly/2fkguA8.
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