Discovery of <i>Omecamtiv Mecarbil</i> the First, Selective, Small Molecule Activator of Cardiac Myosin

Morgan, Bradley; Muci, Alexander R.; Lu, Pu-Ping; Qian, Xiangping; Tochimoto, Todd; Smith, Whitney W.; Garard, Marc; Kraynack, Erica; Collibee, Scott E.; Suehiro, Ion; Tomasi, Adam L.; Valdez, S. Corey; Wang, Wenyue; Jiang, Hong; Hartman, James J.; Rodrı́guez, Héctor M.; Kawas, Raja; Sylvester, Sheila; Elias, Kathleen A.; Godinez, Guillermo; Lee, Kenneth; Anderson, Robert L.; Sueoka, Sandra H.; Xu, Donghong; Wang, Zhengping; Djordjevic, N.; Malik, Fady I.; Morgans, David J.

doi:10.1021/ml100138q

Cited by 104 publications

(75 citation statements)

References 17 publications

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“…A small-molecule activator specific for cardiac myosin II was discovered in a high-throughput screen for compounds that activate cardiac myosin in a reconstituted sarcomere or myofibril assay (Morgan et al, 2010). Tests of the optimized compound, omecamtiv mecarbil, showed that it accelerates P i release and ATP hydrolysis by cardiac myosin in the presence of actin, but slows P i release and ATP hydrolysis in its absence (Malik et al, 2011).…”

Section: Myosin Activatormentioning

confidence: 99%

Force generation by kinesin and myosin cytoskeletal motor proteins

Kull

Endow

2012

Journal of Cell Science

102

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SummaryKinesins and myosins hydrolyze ATP, producing force that drives spindle assembly, vesicle transport and muscle contraction. How do motors do this? Here we discuss mechanisms of motor force transduction, based on their mechanochemical cycles and conformational changes observed in crystal structures. Distortion or twisting of the central b-sheet -proposed to trigger actininduced P i and ADP release by myosin, and microtubule-induced ADP release by kinesins -is shown in a movie depicting the transition between myosin ATP-like and nucleotide-free states. Structural changes in the switch I region form a tube that governs ATP hydrolysis and P i release by the motors, explaining the essential role of switch I in hydrolysis. Comparison of the motor power strokes reveals that each stroke begins with the force-amplifying structure oriented opposite to the direction of rotation or swing. Motors undergo changes in their mechanochemical cycles in response to small-molecule inhibitors, several of which bind to kinesins by induced fit, trapping the motors in a state that resembles a force-producing conformation. An unusual motor activator specifically increases mechanical output by cardiac myosin, potentially providing valuable information about its mechanism of function. Further study is essential to understand motor mechanochemical coupling and energy transduction, and could lead to new therapies to treat human disease. IntroductionCytoskeletal motors have been intensively studied over the past 25 years, but our understanding of how force is produced by the motors is still incomplete. The first crystal structure of a kinesin motor domain revealed an unexpected structural homology between the kinesins and myosins -the motor domain of both proteins is formed by the same core structural elements, organized in the same way to form the nucleotide-or filament-binding site on opposite sides of the motor domain. These structural elements and their organization are conserved within the kinesin and myosin superfamilies, implying a common mechanism of force generation by the motors. By contrast, the dyneins deviate in overall structure from the kinesins and myosins, and presumably also in their mechanism of energy transduction (Carter et al., 2011;Kon et al., 2011;Kon et al., 2012;Höök and Vallee, 2012;Schmidt et al., 2012). The focus of this Commentary is on the kinesins and myosins, for which more is known regarding the motor force-producing mechanism than for the dyneins. We discuss the mechanochemical cycles of the motors and the conformational changes they undergo, based on crystal structures of the motors in different nucleotide states. We propose possible force-producing mechanisms of the motors and compare their working strokes. We also discuss smallmolecule inhibitors of the kinesins and an activator of myosin, whose analysis has resulted in further insights into motor function. Further information on kinesin inhibitors can be found in a recent review (Good et al., 2011).

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Section: Myosin Activatormentioning

confidence: 99%

Force generation by kinesin and myosin cytoskeletal motor proteins

Kull

Endow

2012

Journal of Cell Science

102

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“…Indeed, interactions with these steps may provide several options to regulate contractility (Solaro 2009;Solaro 2010;Sun et al 2008). Probably the best of these strategies may be the application of myosin activators which increase the force of contraction by interacting directly with the myosin heavy chain, as omecamtiv mecarbil, the first selective cardiac myosin activator, does (Morgan et al 2010). …”

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confidence: 99%

“…CK-1213296 was free of this effect, but inhibited the CYP 1A2 enzyme. All side-effects were successfully eliminated from CK-1317138, and the optimized structure was achieved by CK-1827452, omecamtiv mecarbil (Morgan et al 2010). This latter molecule was more potent by one order of magnitude than its ancestor, CK-1317138 .…”

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confidence: 99%

The myosin activator omecamtiv mecarbil: a promising new inotropic agent

Nánási

Váczi

Papp

2016

Can. J. Physiol. Pharmacol.

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Heart failure became a leading cause of mortality in the past few decades with a progressively increasing prevalence. Its current therapy is restricted largely to the suppression of the sympathetic activity and the renin–angiotensin system in combination with diuretics. This restrictive strategy is due to the potential long-term adverse effects of inotropic agents despite their effective influence on cardiac function when employed for short durations. Positive inotropes include inhibitors of the Na+/K+ pump, β-receptor agonists, and phosphodiesterase inhibitors. Theoretically, Ca2+ sensitizers may also increase cardiac contractility without resulting in Ca2+ overload; nevertheless, their mechanism of action is frequently complicated by other pleiotropic effects. Recently, a new positive inotropic agent, the myosin activator omecamtiv mecarbil, has been developed. Omecamtiv mecarbil binds directly to β-myosin heavy chain and enhances cardiac contractility by increasing the number of the active force-generating cross-bridges, presumably without major off-target effects. This review focuses on recent in vivo and in vitro results obtained with omecamtiv mecarbil, and discusses its mechanism of action at a molecular level. Based on clinical data, omecamtiv mecarbil is a promising new tool in the treatment of systolic heart failure.

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“…Omecamtiv mecarbil, ativador seletivo da miosina cardíaca, é a primeira molécula de uma nova classe de drogas inotrópicas positivas que age por ativação direta da miosina cardíaca, destituída de efeitos indesejáveis, como o aumento do consumo de oxigênio, arritmia e aumento da frequência cardíaca 308,309 . Estudos recentes de fase II demonstram que esta medicação pode melhorar a função cardíaca 310,311 , porém não existem grandes estudos clínicos com desfechos de mortalidade e análise de segurança.…”

Section: Ativadores Da Miosina Cardíaca (Omecamtiv Mecarbil)unclassified

Atualização da Diretriz Brasileira de Insuficiência Cardíaca Crônica - 2012

2012

Arquivos Brasileiros De Cardiologia

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Discovery of Omecamtiv Mecarbil the First, Selective, Small Molecule Activator of Cardiac Myosin

Cited by 104 publications

References 17 publications

Force generation by kinesin and myosin cytoskeletal motor proteins

Force generation by kinesin and myosin cytoskeletal motor proteins

The myosin activator omecamtiv mecarbil: a promising new inotropic agent

Atualização da Diretriz Brasileira de Insuficiência Cardíaca Crônica - 2012

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