Novel 1,3,4-Selenadiazole-Containing Kidney-Type Glutaminase Inhibitors Showed Improved Cellular Uptake and Antitumor Activity

Abstract

Kidney-type glutaminase [KGA/isoenzyme glutaminase C (GAC)] is becoming an important tumor metabolism target in cancer chemotherapy. Its allosteric inhibitor, CB839, showed early promise in cancer therapeutics but limited efficacy in in vivo cancer models. To improve the in vivo activity, we explored a bioisostere replacement of the sulfur atom in bis-2-(5-phenylacetamido-1,2,4-thiadiazol)­ethyl sulfide and CB839 analogues with selenium using a novel synthesis of the selenadiazole moiety from carboxylic acids or nitriles. The resulting selenadiazole compounds showed enhanced KGA inhibition, more potent induction of reactive oxygen species, improved inhibition of cancer cells, and higher cellular and tumor accumulation than the corresponding sulfur-containing molecules. However, both CB839 and its selenium analogues show incomplete inhibition of the tested cancer cells, and a partial reduction in tumor size was observed in both the glutamine-dependent HCT116 and aggressive H22 liver cancer xenograft models. Despite this, tumor tissue damage and prolonged survival were observed in animals treated with the selenium analogue of CB839.

HRD1 inhibits fatty acid oxidation and tumorigenesis by ubiquitinating CPT2 in triple‐negative breast cancer

“…After 5 days, the transplanted mice were treated with CB839 via subcutaneous injection (1 mg·mL −1 ; 0.2 mL) or vehicle on a daily basis for 14 consecutive days. The drugs were composed of 5% ethanol, 5% Tween 20, 10% polyethylene glycol (PEG) 400, and 3% F68 in PBS [25]. At 21 days, all mice were euthanized, and tumors were isolated.…”

Targeting Glutaminolysis: New Perspectives to Understand Cancer Development and Novel Strategies for Potential Target Therapies

“…Another widely used glutaminase inhibitor is compound 968, a dibenzophenanthridine, which is first reported to be a GAC inhibitor and repressed oncogenic transformation in breast cancer cells, but is lately found by Lukey et al to be a panglutaminase inhibitor with a moderate selectivity for GLS2 (65, 78). Recently, more potent GLS inhibitors were investigated, including CB-839 selenadiazole-derivatives CPD-20, CPD-23 (131), and Physapubescin I (132). Structures of selected inhibitors and the allosteric binding of GLS1 with BPTES and CB-839 are shown in Figure 3 (66).…”

Targeting Altered Energy Metabolism in Colorectal Cancer: Oncogenic Reprogramming, the Central Role of the TCA Cycle and Therapeutic Opportunities

“…Therefore, synergistic effects of GLS inhibitors in combination with additional metabolic modulators might be the subject of future research. The recently developed CB-839 derivatives CPD-20 and CPD-23 exhibit a stronger inhibition of GLS and better tumor accumulation, resulting in improved antitumorigenic effects [ 191 , 192 ].…”