Cytokinetics Announces Publication Relating to Novel Smooth Muscle Myosin Inhibitor
November 07 2016 - 7:30AM
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.”
About Cytokinetics
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.
Forward-Looking Statements
This press release contains forward-looking
statements for purposes of the Private Securities Litigation Reform
Act of 1995 (the "Act"). Cytokinetics disclaims any intent or
obligation to update these forward-looking statements, and claims
the protection of the Act's Safe Harbor for forward-looking
statements. Examples of such statements include, but are not
limited to, statements relating to Cytokinetics’ and its partners’
research and development activities; the potential for
Cytokinetics’ technology platforms and the properties and potential
efficacy and safety profile of Cytokinetics' drug candidates. Such
statements are based on management's current expectations, but
actual results may differ materially due to various risks and
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difficulties or delays in the development, testing, regulatory
approvals for trial commencement, progression or product sale or
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including risks that current and past results of clinical trials or
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Contact:
Cytokinetics
Diane Weiser
Vice President, Corporate Communications, Investor Relations
(415) 290-7757
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