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

Abstract

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.

Molecular dynamics simulations of the conformational plasticity in the active pocket of salt-inducible kinase 2 (SIK2) multi-state binding with bosutinib

“…This piperazine region was a surface-exposed portion of the inhibitors [ [11] , [12] , [96] ]. However, the fragment in the solvent environment can be used to improve the bioavailability [ [97] , [98] ]. In summary, the SIK2 conformation should be stable when bosutinib is bound to the ATP-binding site.…”

Regio- and Diastereoselective 1,3-Dipolar Cycloadditions of 1,2,4-Triazin-1-ium Ylides: a Straightforward Synthetic Route to Polysubstituted Pyrrolo[2,1-f][1,2,4]triazines

“… 32 , 33 The S -alkyl substituents can be utilized in cross-coupling reactions 33 , 34 or after oxidation, used in nucleophilic substitutions. 35 , 36 Therefore, the substrate scope of the starting triazines is immense, opening an easy access to diverse 1-alkyl-1,2,4-triazinium salts.…”

Structure-Enabled Discovery of Novel Macrocyclic Inhibitors Targeting Glutaminase 1 Allosteric Binding Site

“…2-(3-(Pent-4-enamido)phenyl)acetic acid (19). To a solution of methyl 2-(3-(pent-4-enamido)phenyl)acetate 18 (6.33 g, 25.60 mmol) in ethanol (50 mL) was added 2 N NaOH aqueous solution (5.97 g, 25.60 mmol).…”