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1.  Fast Skeletal Muscle Troponin Activator tirasemtiv Increases Muscle Function and Performance in the B6SJL-SOD1G93A ALS Mouse Model 
PLoS ONE  2014;9(5):e96921.
Amyotrophic Lateral Sclerosis (ALS) is a motor neuron disease characterized by progressive motor neuron loss resulting in muscle atrophy, declining muscle function, and eventual paralysis. Patients typically die from respiratory failure 3 to 5 years from the onset of symptoms. Tirasemtiv is a fast skeletal troponin activator that sensitizes the sarcomere to calcium; this mechanism of action amplifies the response of muscle to neuromuscular input producing greater force when nerve input is reduced. Here, we demonstrate that a single dose of tirasemtiv significantly increases submaximal isometric force, forelimb grip strength, grid hang time, and rotarod performance in a female transgenic mouse model (B6SJL-SOD1G93A) of ALS with functional deficits. Additionally, diaphragm force and tidal volume are significantly higher in tirasemtiv-treated female B6SJL-SOD1G93A mice. These results support the potential of fast skeletal troponin activators to improve muscle function in neuromuscular diseases.
doi:10.1371/journal.pone.0096921
PMCID: PMC4013064  PMID: 24805850
2.  Activation of fast skeletal muscle troponin as a potential therapeutic approach for treating neuromuscular diseases 
Nature medicine  2012;18(3):452-455.
Limited neuromuscular input results in muscle weakness in neuromuscular disease either because of a reduction in the density of muscle innervation, the rate of neuromuscular junction activation or the efficiency of synaptic transmission1. We developed a small molecule fast skeletal troponin activator, CK-2017357, as a means to increase muscle strength by amplifying the response of muscle when neuromuscular input is diminished secondary to a neuromuscular disease. Binding selectively to the fast skeletal troponin complex, CK-2017357 slows the rate of calcium release from troponin C and sensitizes muscle to calcium. As a consequence, the force-calcium relationship of muscle fibers shifts leftwards as does the force-frequency relationship of a nerve-muscle pair. In vitro and in vivo, CK-2017357 increases the production of force at sub-maximal stimulation rates. Importantly, we show that sensitization of the fast skeletal troponin complex to calcium improves muscle force and grip strength immediately after single doses of CK-2017357 in a model of neuromuscular disease, myasthenia gravis. Troponin activation may provide a new therapeutic approach to improve physical activity in diseases where neuromuscular function is compromised.
doi:10.1038/nm.2618
PMCID: PMC3296825  PMID: 22344294
3.  Smooth Muscle Myosin Inhibition: A Novel Therapeutic Approach for Pulmonary Hypertension 
PLoS ONE  2012;7(5):e36302.
Objective
Pulmonary hypertension remains a major clinical problem despite current therapies. In this study, we examine for the first time a novel pharmacological target, smooth muscle myosin, and determine if the smooth muscle myosin inhibitor, CK-2019165 (CK-165) ameliorates pulmonary hypertension.
Materials and Methods
Six domestic female pigs were surgically instrumented to measure pulmonary blood flow and systemic and pulmonary vascular dynamics. Pulmonary hypertension was induced by hypoxia, or infusion of the thromboxane analog (U-46619, 0.1 µg/kg/min, i.v.). In rats, chronic pulmonary hypertension was induced by monocrotaline.
Results
CK-165 (4 mg/kg, i.v.) reduced pulmonary vascular resistance by 22±3 and 28±6% from baseline in hypoxia and thromboxane pig models, respectively (p<0.01 and 0.01), while mean arterial pressure also fell and heart rate rose slightly. When CK-165 was delivered via inhalation in the hypoxia model, pulmonary vascular resistance fell by 17±6% (p<0.05) while mean arterial pressure and heart rate were unchanged. In the monocrotaline model of chronic pulmonary hypertension, inhaled CK-165 resulted in a similar (18.0±3.8%) reduction in right ventricular systolic pressure as compared with sildenafil (20.3±4.5%).
Conclusion
Inhibition of smooth muscle myosin may be a novel therapeutic target for treatment of pulmonary hypertension.
doi:10.1371/journal.pone.0036302
PMCID: PMC3341368  PMID: 22563487
4.  Discovery of Omecamtiv Mecarbil the First, Selective, Small Molecule Activator of Cardiac Myosin 
ACS Medicinal Chemistry Letters  2010;1(9):472-477.
We report the design, synthesis, and optimization of the first, selective activators of cardiac myosin. Starting with a poorly soluble, nitro-aromatic hit compound (1), potent, selective, and soluble myosin activators were designed culminating in the discovery of omecamtiv mecarbil (24). Compound 24 is currently in clinical trials for the treatment of systolic heart failure.
doi:10.1021/ml100138q
PMCID: PMC4007828  PMID: 24900233
Omecamtiv mecarbil; small molecule enzyme activator; cardiac myosin; systolic heart failure
5.  Discovery of the First Potent and Selective Inhibitor of Centromere-Associated Protein E: GSK923295 
Inhibition of mitotic kinesins represents a novel approach for the discovery of a new generation of anti-mitotic cancer chemotherapeutics. We report here the discovery of the first potent and selective inhibitor of centromere-associated protein E (CENP-E) 3-chloro-N-{(1S)-2-[(N,N-dimethylglycyl)amino]-1-[(4-{8-[(1S)-1-hydroxyethyl]imidazo[1,2-a]pyridin-2-yl}phenyl)methyl]ethyl}-4-[(1-methylethyl)oxy]benzamide (GSK923295; 1), starting from a high-throughput screening hit, 3-chloro-4-isopropoxybenzoic acid 2. Compound 1 has demonstrated broad antitumor activity in vivo and is currently in human clinical trials.
doi:10.1021/ml900018m
PMCID: PMC4007900  PMID: 24900171
CENP-E; inhibitor; GSK923295; mitotic kinesin
6.  Effective killing of the human pathogen Candida albicans by a specific inhibitor of non-essential mitotic kinesin Kip1p 
Molecular Microbiology  2007;65(2):347-362.
Kinesins from the bipolar (Kinesin-5) family are conserved in eukaryotic organisms and play critical roles during the earliest stages of mitosis to mediate spindle pole body separation and formation of a bipolar mitotic spindle. To date, genes encoding bipolar kinesins have been reported to be essential in all organisms studied. We report the characterization of CaKip1p, the sole member of this family in the human pathogenic yeast Candida albicans. C. albicans Kip1p appears to localize to the mitotic spindle and loss of CaKip1p function interferes with normal progression through mitosis. Inducible excision of CaKIP1 revealed phenotypes unique to C. albicans, including viable homozygous Cakip1 mutants and an aberrant spindle morphology in which multiple spindle poles accumulate in close proximity to each other. Expression of the C. albicans Kip1 motor domain in Escherichia coli produced a protein with microtubule-stimulated ATPase activity that was inhibited by an aminobenzothiazole (ABT) compound in an ATP-competitive fashion. This inhibition results in ‘rigor-like’, tight association with microtubules in vitro. Upon treatment of C. albicans cells with the ABT compound, cells were killed, and terminal phenotype analysis revealed an aberrant spindle morphology similar to that induced by loss of the CaKIP1 gene. The ABT compound discovered is the first example of a fungal spindle inhibitor targeted to a mitotic kinesin. Our results also show that the non-essential nature and implementation of the bipolar motor in C. albicans differs from that seen in other organisms, and suggest that inhibitors of a non-essential mitotic kinesin may offer promise as cidal agents for antifungal drug discovery.
doi:10.1111/j.1365-2958.2007.05787.x
PMCID: PMC1976386  PMID: 17573815

Results 1-6 (6)