Discovery of a Thiadiazole–Pyridazine-Based Allosteric Glutaminase 1 Inhibitor Series That Demonstrates Oral Bioavailability and Activity in Tumor Xenograft Models

Tumors have evolved a variety
of methods to reprogram conventional
metabolic pathways to favor their own nutritional needs, including
glutaminolysis, the first step of which is the hydrolysis of glutamine
to glutamate by the amidohydrolase glutaminase 1 (GLS1). A GLS1 inhibitor
could potentially target certain cancers by blocking the tumor cell’s
ability to produce glutamine-derived nutrients. Starting from the
known GLS1 inhibitor bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)­ethyl
sulfide, we describe the medicinal chemistry evolution of a series
from lipophilic inhibitors with suboptimal physicochemical and pharmacokinetic
properties to cell potent examples with reduced molecular weight and
lipophilicity, leading to compounds with greatly improved oral exposure
that demonstrate in vivo target engagement accompanied by activity
in relevant disease models.