title: Cardiac myosin activation: a potential therapeutic approach for systolic heart failure.
abstract: Decreased cardiac contractility is a central feature of systolic heart failure. Existing drugs increase cardiac contractility indirectly through signaling cascades but are limited by their mechanism-related adverse effects. To avoid these limitations, we previously developed omecamtiv mecarbil, a small-molecule, direct activator of cardiac myosin. Here, we show that it binds to the myosin catalytic domain and operates by an allosteric mechanism to increase the transition rate of myosin into the strongly actin-bound force-generating state. Paradoxically, it inhibits adenosine 5'-triphosphate turnover in the absence of actin, which suggests that it stabilizes an actin-bound conformation of myosin. In animal models, omecamtiv mecarbil increases cardiac function by increasing the duration of ejection without changing the rates of contraction. Cardiac myosin activation may provide a new therapeutic approach for systolic heart failure.
authors.affiliation: Preclinical Research and Development, Cytokinetics, Inc., South San Francisco, CA 94080, USA. fmalik@cytokinetics.com
authors.forename: Fady I
authors.initials: FI
authors.lastname: Malik
authors.forename: James J
authors.initials: JJ
authors.lastname: Hartman
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Elias
authors.forename: Bradley P
authors.initials: BP
authors.lastname: Morgan
authors.forename: Hector
authors.initials: H
authors.lastname: Rodriguez
authors.forename: Katjusa
authors.initials: K
authors.lastname: Brejc
authors.forename: Robert L
authors.initials: RL
authors.lastname: Anderson
authors.forename: Sandra H
authors.initials: SH
authors.lastname: Sueoka
authors.forename: Kenneth H
authors.initials: KH
authors.lastname: Lee
authors.forename: Jeffrey T
authors.initials: JT
authors.lastname: Finer
authors.forename: Roman
authors.initials: R
authors.lastname: Sakowicz
authors.forename: Ramesh
authors.initials: R
authors.lastname: Baliga
authors.forename: David R
authors.initials: DR
authors.lastname: Cox
authors.forename: Marc
authors.initials: M
authors.lastname: Garard
authors.forename: Guillermo
authors.initials: G
authors.lastname: Godinez
authors.forename: Raja
authors.initials: R
authors.lastname: Kawas
authors.forename: Erica
authors.initials: E
authors.lastname: Kraynack
authors.forename: David
authors.initials: D
authors.lastname: Lenzi
authors.forename: Pu Ping
authors.initials: PP
authors.lastname: Lu
authors.forename: Alexander
authors.initials: A
authors.lastname: Muci
authors.forename: Congrong
authors.initials: C
authors.lastname: Niu
authors.forename: Xiangping
authors.initials: X
authors.lastname: Qian
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Pierce
authors.forename: Maria
authors.initials: M
authors.lastname: Pokrovskii
authors.forename: Ion
authors.initials: I
authors.lastname: Suehiro
authors.forename: Sheila
authors.initials: S
authors.lastname: Sylvester
authors.forename: Todd
authors.initials: T
authors.lastname: Tochimoto
authors.forename: Corey
authors.initials: C
authors.lastname: Valdez
authors.forename: Wenyue
authors.initials: W
authors.lastname: Wang
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Katori
authors.forename: David A
authors.initials: DA
authors.lastname: Kass
authors.forename: You-Tang
authors.initials: YT
authors.lastname: Shen
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Vatner
authors.forename: David J
authors.initials: DJ
authors.lastname: Morgans
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism; D000199:Actins / Q000378:metabolism; D000251:Adenosine Triphosphatases / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000494:Allosteric Regulation; D000818:Animals; D001665:Binding Sites; D002118:Calcium / Q000378:metabolism; D024722:Cardiac Myosins / Q000737:chemistry / Q000378:metabolism*; D002302:Cardiac Output / Q000187:drug effects; D004285:Dogs; D005260:Female; D054143:Heart Failure, Systolic / Q000188:drug therapy* / Q000503:physiopathology; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000502:physiology; D010710:Phosphates / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D020033:Protein Isoforms / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014508:Urea / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D016277:Ventricular Function, Left / Q000187:drug effects
chemical_list: D000199:Actins; D000318:Adrenergic beta-Agonists; D010710:Phosphates; D020033:Protein Isoforms; C547293:omecamtiv mecarbil; D000255:Adenosine Triphosphate; D014508:Urea; D000251:Adenosine Triphosphatases; D024722:Cardiac Myosins; D007545:Isoproterenol; D002118:Calcium