EPZ031686 is a potent and orally active SMYD3 inhibitor with an IC₅₀ value of 3nM. EPZ031686 noncompetitively inhibits both SAM and MEKK2, with Ki values of approximately 1.2nM and 1.1nM, respectively[1]. By enhancing PPARγ expression, EPZ031686 induces white adipose tissue browning and adaptive thermogenesis, offering a potential therapeutic strategy for obesity[2]. EPZ031686 shows potential in suppressing tumor development[3-4].
In vitro, treatment of HCT116 colorectal cancer cells and MDA-MB-231 breast cancer cells with EPZ031686 (0.5–50μM) for 48–72 hours significantly reduced SMYD3-mediated ERK1/2 phosphorylation and induced PARP cleavage, thereby inhibiting tumor cell proliferation and promoting apoptosis[5].
In vivo, daily intraperitoneal administration of EPZ031686 (20mg/kg) for 7 consecutive days in mice significantly upregulated uncoupling protein 1 (UCP1) expression in inguinal white adipose tissue (iWAT) and brown adipose tissue (BAT), while activating the transcription of thermogenic genes (Ucp1, Ppargc1a, Cpt2, Cpt1a, Cpt1b), thereby promoting white fat browning and adaptive thermogenesis[2]. A single dose of EPZ031686 (1mg/kg intravenously or 5–50mg/kg orally) in male CD-1 mice resulted in moderate clearance (27±3.9mL/min/kg), a large steady-state volume of distribution (2.3±0.29L/kg), and a terminal half-life of 1.7±0.13 hours[1].
References:
[1] Mitchell LH, Boriack-Sjodin PA, Smith S, et al. Novel Oxindole Sulfonamides and Sulfamides: EPZ031686, the First Orally Bioavailable Small Molecule SMYD3 Inhibitor. ACS Med Chem Lett. 2015 Aug 27;7(2):134-8.
[2] Shu M, Ma Y, Zhao D, et al. Loss of histone methyltransferase Smyd3 triggers WAT browning and adaptive thermogenesis via enhancing PPARγ expression in a H4K20me3-dependent manner. J Transl Med. 2025 Oct 1;23(1):1041.
[3] Rubio-Tomás T. Novel insights into SMYD2 and SMYD3 inhibitors: from potential anti-tumoural therapy to a variety of new applications. Mol Biol Rep. 2021 Nov;48(11):7499-7508.
[4] Rajajeyabalachandran G, Kumar S, Murugesan T, et al. Therapeutical potential of deregulated lysine methyltransferase SMYD3 as a safe target for novel anticancer agents. Expert Opin Ther Targets. 2017 Feb;21(2):145-157.
[5] Parenti MD, Naldi M, Manoni E, et al. Discovery of the 4-aminopiperidine-based compound EM127 for the site-specific covalent inhibition of SMYD3. Eur J Med Chem. 2022 Dec 5;243:114683.
EPZ031686是一种有效且具有口服活性的SMYD3抑制剂，其IC50值为3nM，EPZ031686能够以非竞争性方式同时抑制SAM和MEKK2，其Ki值分别约为1.2nM和1.1nM[1]。EPZ031686可通过增强PPARγ表达，从而诱导白色脂肪棕色化和适应性产热，为肥胖症的治疗提供了新的潜在策略[2]。EPZ031686还具有抑制肿瘤发育的潜力[3-4]。
在体外，EPZ031686（0.5–50μM）处理HCT116结直肠癌细胞和MDA-MB-231乳腺癌细胞48–72小时，显著降低SMYD3介导的ERK1/2磷酸化水平，同时诱导PARP蛋白切割，从而抑制肿瘤细胞增殖并促进凋亡[5]。
在体内，EPZ031686（20mg/kg）连续7天腹腔注射处理小鼠，显著增强腹股沟白色脂肪组织（iWAT）和棕色脂肪组织（BAT）中解偶联蛋白1（UCP1）的蛋白表达水平，同时促进产热基因（Ucp1、Ppargc1a、Cpt2、Cpt1a、Cpt1b）的转录激活，从而诱导白色脂肪棕色化和适应性产热[2]。EPZ031686（1mg/kg静脉注射或5-50mg/kg口服）单次给药处理雄性CD-1小鼠，显示中等清除率（27±3.9mL/min/kg）和较大的稳态分布容积（2.3±0.29L/kg），终末半衰期为1.7±0.13小时[1]。