YKL-05-099 is a highly selective small molecule inhibitor of salt-inducible kinases (SIK1: IC50 = 10nM; SIK2: IC50 = 40nM; SIK3: IC50 = 20nM) [1]. By blocking SIK-mediated phosphorylation of HDACs and CRTCs, YKL-05-099 promotes the nuclear translocation of these transcriptional regulators, thereby altering downstream gene expression [2-3]. YKL-05-099 is primarily used in research on bone metabolism, inflammation, and tumorigenesis [4].
In MLL-rearranged leukemia cells, YKL-05-099 (1nM-10μM; 72h) inhibits the growth of cells by modulating SIK3-mediated regulation of HDAC4 [5]. In primary human adipocytes YKL-05-099 (3-30μM; 1h) significantly inhibited glucose uptake, reducing both basal and submaximally insulin-stimulated uptake [6].
In KPC cell subcutaneous tumor-bearing mice model, YKL-05-099 (8mg/kg; ip; 26d) significantly enhanced the antitumor effect of gemcitabine by augmenting its cytotoxicity and promoting ferroptosis, as evidenced by decreased Ki67 expression and increased 4-HNE and Fe²⁺ levels [7]. In collagen-induced arthritis (CIA) mouse model, treatment with YKL-05-099 (20mg/kg; ip; single injection) significantly reduced joint and bone destruction and immune cell infiltration, reduced TUNEL⁺ apoptotic cells in synovial tissue, and enhanced the clearance of apoptotic cells by macrophages, thereby improving the symptoms of rheumatoid arthritis [8].
References:
[1]. Sundberg T B, Liang Y, Wu H, et al. Development of chemical probes for investigation of salt-inducible kinase function in vivo[J]. ACS chemical biology, 2016, 11(8): 2105-2111.
[2]. Jagannath A, Taylor L, Ru Y, et al. The multiple roles of salt-inducible kinases in regulating physiology[J]. Physiological reviews, 2023, 103(3): 2231-2269.
[3]. Wein M N, Liang Y, Goransson O, et al. SIKs control osteocyte responses to parathyroid hormone[J]. Nature communications, 2016, 7(1): 13176.
[4]. Momenzadeh K, Yeritsyan D, Abbasian M, et al. Stimulation of fracture mineralization by salt-inducible kinase inhibitors[J]. Frontiers in Bioengin
[5]. Tarumoto Y, Lin S, Wang J, et al. The Salt-Inducible Kinase inhibitor YKL-05-099 suppresses MEF2C function and acute myeloid leukemia progression in vivo[J]. bioRxiv, 2019: 636969.
[6]. Säll J, Lindahl M, Fritzen A M, et al. Salt‐inducible kinases are required for glucose uptake and insulin signaling in human adipocytes[J]. Obesity, 2023, 31(10): 2515-2529.
[7]. Zhang H, Ma T, Wen X, et al. SIK1 promotes ferroptosis resistance in pancreatic cancer via HDAC5-STAT6-SLC7A11 axis[J]. Cancer Letters, 2025, 623: 217726.
[8]. Lee M, Kim M K, Mo S, et al. Inhibition of salt-inducible kinases resolves autoimmune arthritis by promoting macrophage efferocytosis[J]. Signal Transduction and Targeted Therapy, 2025, 10(1): 293.
YKL-05-099是一种高选择性盐诱导激酶（SIK1: IC50 = 10nM; SIK2: IC50 = 40nM; SIK3: IC50 = 20nM）的小分子抑制剂 [1]。通过阻断SIK介导的HDAC和CRTC磷酸化，YKL-05-099促进这些转录调控因子的核转位，从而改变下游基因的表达 [2-3]。YKL-05-099主要用于骨代谢、炎症和肿瘤发生研究 [4]。
在MLL重排的白血病细胞中，YKL-05-099（1nM-10μM; 72h）通过调节SIK3介导的HDAC4调控来抑制细胞生长 [5]。在原代人脂肪细胞中，YKL-05-099（3-30μM；1h）显著抑制葡萄糖摄取，降低基础和亚最大胰岛素刺激的摄取 [6]。
在KPC细胞皮下移植瘤小鼠模型中，YKL-05-099（8mg/kg；ip；26d）显著增强了gemcitabine的抗肿瘤作用，增强了其细胞毒性并促进了铁死亡，其证据是Ki67表达降低、4-HNE和Fe²⁺水平升高 [7]。在胶原诱导性关节炎（CIA）小鼠模型中，用YKL-05-099（20mg/kg；ip；单次注射）治疗可显著减少关节和骨骼破坏以及免疫细胞浸润，减少滑膜组织中的TUNEL⁺凋亡细胞，增强巨噬细胞对凋亡细胞的清除，从而改善类风湿性关节炎症状 [8]。