Diabetes & metabolism journal · 2026
Development and Preclinical Evaluation of Novel STK3/4 Inhibitors with Anti-Obesity Potential.
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Song Woonyoung, Kim Heeseong, Joh Yoonjoe, Lee Sangwoo, Cho Yoon Keun, Lee Jeonghun, Park Gyeongran, Kim Taeeun, Kim Sangseob, Lee Junhyuck, Kim Young Gwan, Gam Jongsik, Lim Bumhee, Sun Woong, Ha Eun-Hee, Hong Ki Yong, Lee Yun-Hee, Lee Jeeyeon
Аннотация
BACKGROUND: Obesity is associated with impaired adipocyte metabolism driven in part by mitochondrial dysfunction. Serine/threonine-protein kinase 3 (STK3) and STK4 promote mitophagy, leading to reduced mitochondrial mass in adipose tissue. Thus, inhibition of STK3/4 represents a potential therapeutic strategy for obesity and related metabolic disorders.
METHODS: Two novel STK3/STK4 inhibitors, LL-M and LL-P, were identified from a focused small-molecule library using a fluorescence-based titration assay. Their effects on STK3/4 signaling and mitophagy were evaluated in C3H10T1/2 adipocytes. In vivo efficacy was assessed in male C57BL/6J mice fed either a normal chow diet or a high-fat diet (HFD), followed by a 2-week treatment with LL-M or LL-P. Metabolic outcomes, including body weight, glucose tolerance, and energy expenditure, were assessed.
RESULTS: In adipocytes, LL-M and LL-P effectively suppressed STK3/4 signaling, reduced BCL2 interacting protein 3 (BNIP3)-mediated mitophagy, and increased mitochondrial metabolic activity. In HFD-fed mice, treatment with either compound attenuated body-weight gain, improved glucose tolerance, and enhanced energy expenditure.
CONCLUSION: Pharmacological inhibition of STK3/4 by LL-M and LL-P restores mitochondrial function through suppression of BNIP3-mediated mitophagy, leading to improved adipocyte function and metabolic outcomes. These findings support the therapeutic potential of LL-M and LL-P as small-molecule candidates for the treatment of obesity and related metabolic disorders.
METHODS: Two novel STK3/STK4 inhibitors, LL-M and LL-P, were identified from a focused small-molecule library using a fluorescence-based titration assay. Their effects on STK3/4 signaling and mitophagy were evaluated in C3H10T1/2 adipocytes. In vivo efficacy was assessed in male C57BL/6J mice fed either a normal chow diet or a high-fat diet (HFD), followed by a 2-week treatment with LL-M or LL-P. Metabolic outcomes, including body weight, glucose tolerance, and energy expenditure, were assessed.
RESULTS: In adipocytes, LL-M and LL-P effectively suppressed STK3/4 signaling, reduced BCL2 interacting protein 3 (BNIP3)-mediated mitophagy, and increased mitochondrial metabolic activity. In HFD-fed mice, treatment with either compound attenuated body-weight gain, improved glucose tolerance, and enhanced energy expenditure.
CONCLUSION: Pharmacological inhibition of STK3/4 by LL-M and LL-P restores mitochondrial function through suppression of BNIP3-mediated mitophagy, leading to improved adipocyte function and metabolic outcomes. These findings support the therapeutic potential of LL-M and LL-P as small-molecule candidates for the treatment of obesity and related metabolic disorders.