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.
Hypercontractility
of the cardiac sarcomere may be essential for
the underlying pathological hypertrophy and fibrosis in genetic hypertrophic
cardiomyopathies. Aficamten (CK-274) is a novel cardiac myosin inhibitor
that was discovered from the optimization of indoline compound 1. The important advancement of the optimization was discovery
of an Indane analogue (12) with a less restrictive structure–activity
relationship that allowed for the rapid improvement of drug-like properties.
Aficamten was designed to provide a predicted human half-life (t
1/2) appropriate for once a day (qd) dosing,
to reach steady state within two weeks, to have no substantial cytochrome
P450 induction or inhibition, and to have a wide therapeutic window in vivo with a clear pharmacokinetic/pharmacodynamic relationship.
In a phase I clinical trial, aficamten demonstrated a human t
1/2 similar to predictions and was able to reach
steady state concentration within the desired two-week window.
The discovery of reldesemtiv, a second-generation fast skeletal muscle troponin activator (FSTA) that increases force production at submaximal stimulation frequencies, is reported. Property-based optimization of high throughput screening hit 1 led to compounds with improved free exposure and in vivo muscle activation potency compared to the first-generation FSTA, tirasemtiv. Reldesemtiv demonstrated increased muscle force generation in a phase 1 clinical trial and is currently being evaluated in clinical trials for the treatment of amyotrophic lateral sclerosis.
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