NH‐sulfoximine: A novel pharmacological inhibitor of the mitochondrial F₁F_o‐ATPase, which suppresses viability of cancerous cells

Abstract

Background and Purpose: The mitochondrial F 1 F o-ATPsynthase is pivotal for cellular homeostasis. When respiration is perturbed, its mode of action everts becoming an F 1 F o-ATPase and therefore consuming rather producing ATP. Such a reversion is an obvious target for pharmacological intervention to counteract pathologies. Despite this, tools to selectively inhibit the phases of ATP hydrolysis without affecting the production of ATP remain scarce. Here, we report on a newly synthesised chemical, the NH-sulfoximine (NHS), which achieves such a selectivity. Experimental Approach: The chemical structure of the F 1 F o-ATPase inhibitor BTB-06584 was used as a template to synthesise NHS. We assessed its pharmacology in human neuroblastoma SH-SY5Y cells in which we profiled ATP levels, redox signalling, autophagy pathways and cellular viability. NHS was given alone or in combination with either the glucose analogue 2-deoxyglucose (2-DG) or the chemotherapeutic agent etoposide. Key Results: NHS selectively blocks the consumption of ATP by mitochondria leading a subtle cytotoxicity associated via the concomitant engagement of autophagy which impairs cell viability. NHS achieves such a function independently of the F 1 F o-ATPase inhibitory factor 1 (IF1). Conclusion and Implications: The novel sulfoximine analogue of BTB-06584, NHS, acts as a selective pharmacological inhibitor of the mitochondrial F 1 F o-ATPase. NHS,

In silico approaches to study the human asparagine synthetase: An insight of the interaction between the enzyme active sites and its substrates

“…The sulfoximine compounds are profoundly known for their anti-cancer activity. It has been reported that adenylated sulfoximine is ASNS inhibitors and adenylated sulfoximine 7b has been used to define the enzymes inhibition activity in MOT4 cell lines [ 37 ]. Sulfoximine adenylate was used to dock with the C -terminal region of human ASNS.…”

F-ATP synthase inhibitory factor 1 regulates metabolic reprogramming involving its interaction with c-Myc and PGC1α

“…Thus, IF1 acts as a novel clinical biomarker of dermatomyositis and a potential metabolic driver of cancer incidence ( 61 ). Novel pharmacological inhibitors of IF1 are developed to counteract pathologies ( 62 ).…”

ATPase Inhibitory Factor-1 Disrupts Mitochondrial Ca2+ Handling and Promotes Pathological Cardiac Hypertrophy through CaMKIIδ

“…Finally, the present work underscores a central role of mitochondria in pathological growth responses in the heart and supports current efforts to design mitochondrial targeted therapies for HF [ 34 , 35 , 36 , 37 ]. IF1 appears to be both an attractive and feasible target for pharmacological modulation as several compounds are currently in various stages of clinical development [ 38 , 39 ].…”