Cytokinetics Announces Publication Relating To Novel Smooth Muscle Myosin Inhibitor

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."

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