Structure-guided discovery of a novel, potent, and orally bioavailable 3,5-dimethylisoxazole aryl-benzimidazole BET bromodomain inhibitor.

The bromodomain and extra-terminal (BET) family of proteins, consisting of the bromodomains containing protein 2 (BRD2), BRD3, BRD4, and the testis-specific BRDT, are key epigenetic regulators of gene transcription and has emerged as an attractive target for anticancer therapy. Herein, we describe the discovery of a novel potent BET bromodomain inhibitor, using a systematic structure-based approach focused on improving potency, metabolic stability, and permeability. The optimized dimethylisoxazole aryl-benzimidazole inhibitor exhibited high potency towards BRD4 and related BET proteins in biochemical and cell-based assays and inhibited tumor growth in two proof-of-concept preclinical animal models.

ASK1 contributes to fibrosis and dysfunction in models of kidney disease.

Oxidative stress is an underlying component of acute and chronic kidney disease. Apoptosis signal-regulating kinase 1 (ASK1) is a widely expressed redox-sensitive serine threonine kinase that activates p38 and c-Jun N-terminal kinase (JNK) mitogen-activated protein kinase kinases, and induces apoptotic, inflammatory, and fibrotic signaling in settings of oxidative stress. We describe the discovery and characterization of a potent and selective small-molecule inhibitor of ASK1, GS-444217, and demonstrate the therapeutic potential of ASK1 inhibition to reduce kidney injury and fibrosis.

Discovery of Dihydrobenzoxazepinone (GS-6615) Late Sodium Current Inhibitor (Late Ii), a Phase II Agent with Demonstrated Preclinical Anti-Ischemic and Antiarrhythmic Properties.

Late sodium current (late I) is enhanced during ischemia by reactive oxygen species (ROS) modifying the Na 1.5 channel, resulting in incomplete inactivation. Compound 4 (GS-6615, eleclazine) a novel, potent, and selective inhibitor of late I, is currently in clinical development for treatment of long QT-3 syndrome (LQT-3), hypertrophic cardiomyopathy (HCM), and ventricular tachycardia-ventricular fibrillation (VT-VF).

Enantioselective cyclization of enamide-ynes and application to the synthesis of the kopsifoline core.

We report the palladium-catalyzed enantioselective cyclization of 1,6-enamidynes to form spirocyclic ring systems. We applied this methodology to the concise synthesis of the skeletal core of the kopsifoline alkaloids.

Enantioselective cyclizations of silyloxyenynes catalyzed by cationic metal phosphine complexes.

The discovery of complementary methods for enantioselective transition metal-catalyzed cyclization with silyloxyenynes has been accomplished using chiral phosphine ligands. Under palladium catalysis, 1,6-silyloxyenynes bearing a terminal alkyne led to the desired five-membered ring with high enantioselectivities (up to 91% ee). As for reactions under cationic gold catalysis, 1,6- and 1,5-silyloxyenynes bearing an internal alkyne furnished the chiral cyclopentane derivatives with excellent enantiomeric excess (up to 94% ee).

Catalytic enantioselective Conia-ene reaction.

An enantioselective intramolecular Conia-ene reaction of beta-dicarbonyl compounds and alkynes to afford methylene cyclopentanes is described. The reaction employs a DTBMSegphos-Pd(II)/Yb(III) dual catalyst system that allows for the asymmetric synthesis of all-carbon quaternary centers and generates a product containing an alkene that can be further manipulated.