Non-orthosteric inhibition of enolase 1 impedes growth of triple-negative breast cancer.

Abstract

Cancer cells exploit and overexpress glycolytic enzymes such as enolase 1 (ENO1) to sustain the Warburg effect, a hallmark of cancer metabolism, which makes ENO1 a compelling therapeutic target. Here, we demonstrate that SU212, a small molecule inhibitor, binds ENO1 and induces its degradation, restricting its intracellular localization. Through these effects, SU212 reduces tumor cell glycolytic activity and glucose uptake and ultimately suppresses tumor growth and metastasis in syngeneic, genetic, and patient-derived xenograft models of triple-negative breast cancer. Further, in a diabetic mouse model, SU212 demonstrated robust anti-tumor efficacy while improving fatty liver conditions and lowering blood glucose. Other glycolytic enzyme inhibitors have been limited by toxicity; thorough pharmacokinetic and toxicity testing of SU212 revealed a favorable drug-like profile with minimal toxicity and no interference with key biological systems. These findings highlight SU212's dual-action potential to disrupt cancer metabolism and address metabolic disorders, offering a transformative approach to cancer therapy.