AUTHOR=Kang Sein , Na Yoon-Ju , Choi Kyoung Jin , Jung Won Hoon , Park Areum , Im Jeonghui , Park Sung Bum , Koh Byumseok , Lee Joo-Youn , Hoe Kwang-Lae , Kim Heung Jae , Shin Sang Joon , Lee Hyuk , Kim Ki Young TITLE=Discovery of a selective dual-specificity tyrosine phosphorylation-regulated kinase 1B inhibitor with anti-adipogenic and anti-diabetic activities JOURNAL=Frontiers in Pharmacology VOLUME=Volume 16 - 2025 YEAR=2025 URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2025.1645033 DOI=10.3389/fphar.2025.1645033 ISSN=1663-9812 ABSTRACT=BackgroundDual-specificity tyrosine phosphorylation-regulated kinase 1B (DYRK1B) is implicated in metabolic diseases, with high expression linked to adipocyte differentiation and metabolic disorders. This study investigated the anti-adipogenic and anti-diabetic effects of a novel selective DYRK1B inhibitor, N-(4-(3-(4-methoxyphenyl)-1H-pyrazolo [3,4-b]pyridin-5-yl) phenyl)acetamide (KS-40070).MethodsThe efficacy of KS-40070 was evaluated using 3T3-L1 cells, adipose-derived mesenchymal stem cells (ADMSC), and diet-induced obesity (DIO) mice.ResultsTreatment with KS-40070 dose-dependently inhibited 3T3-L1 preadipocyte differentiation, reducing key adipogenic transcription factors like PPARγ and C/EBPα, along with related proteins. KS-40070 suppressed lipid accumulation by decreasing Akt-FOXO1A signaling and GSK3β expression. Importantly, these effects were abolished in DYRK1B knockdown cells, confirming DYRK1B's role. In DIO mice, KS-40070 suppressed body weight gain, food consumption, serum lipid levels, and adipose tissue mass. It also improved insulin resistance and glucose intolerance.ConclusionThese findings suggest that inhibiting DYRK1B with agents like KS-40070 presents a promising therapeutic strategy for obesity and type 2 diabetes.