BAY-598

BAY-598 is an aminopyrazolinyl-based selective small-molecule inhibitor targeting the protein SMYD2 (SET and MYND domain-containing protein 2), with a half-maximal inhibitory concentration (IC₅₀) of 27nM^[1]. BAY-598 shows potential for the treatment of schistosomiasis and cancer^[2-3].

In vitro, treatment of non-small cell lung cancer A549 and H460 cells with BAY-598 (15–20nM) in combination with doxorubicin (DOX; 30nM) for 48 hours synergistically inhibited cell viability, invasion, and migration, and promoted apoptosis and G2 phase cell cycle arrest^[4]. Treatment of colorectal cancer HCT 116 and LoVo cells with BAY-598 (10μM) for 48 hours significantly inhibited the methyltransferase activity of SMYD2, reduced the monomethylation level of HNRNPK protein at lysine 422 (K422), thereby weakening the binding ability of HNRNPK to EGFL7 mRNA^[5].

In vivo, in female nude mice bearing A549 cell xenograft tumors, administration of BAY-598 (5mg/kg) via intraperitoneal injection every other day, combined with doxorubicin (2mg/kg) via intraperitoneal injection every five days for 32 days, significantly suppressed the growth of non-small cell lung cancer xenograft tumors^[4]. In nude mice with colorectal cancer patient-derived xenograft (PDX) models, daily intraperitoneal injection of BAY-598 (50mg/kg) combined with daily oral gavage of Apatinib (30mg/kg) for 14 days significantly inhibited angiogenesis in the colorectal cancer xenografts^[5].

References:
[1] Reynoird N, Mazur PK, Stellfeld T, et al. Coordination of stress signals by the lysine methyltransferase SMYD2 promotes pancreatic cancer. Genes Dev. 2016 Apr 1;30(7):772-85.
[2] Whatley KCL, Padalino G, Whiteland H, et al. The repositioning of epigenetic probes/inhibitors identifies new anti-schistosomal lead compounds and chemotherapeutic targets. PLoS Negl Trop Dis. 2019 Nov 15;13(11):e0007693.
[3] Ahmed H, Duan S, Arrowsmith CH, et al. An Integrative Proteomic Approach Identifies Novel Cellular SMYD2 Substrates. J Proteome Res. 2016 Jun 3;15(6):2052-9.
[4] Meng J, Yang W, Li C, et al. Synergistic anticancer effects of SMYD2 inhibitor BAY-598 and doxorubicin in non-small cell lung cancer. Heliyon. 2024 May 29;10(11):e32015.
[5] Eggert E, Hillig RC, Koehr S, et al. Discovery and Characterization of a Highly Potent and Selective Aminopyrazoline-Based in Vivo Probe (BAY-598) for the Protein Lysine Methyltransferase SMYD2. J Med Chem. 2016 May 26;59(10):4578-600.

BAY-598是一种氨基吡唑啉基的选择性小分子抑制剂，靶点为含有SET和MYND结构域的蛋白2（SMYD2），半抑制浓度（IC₅₀）为27nM^[1]。BAY-598具有治疗血吸虫病和癌症的潜力^[2-3]。

在体外，BAY-598(15-20nM)与多柔比星(DOX；30nM)联合处理非小细胞肺癌A549和H460细胞48小时，能协同抑制细胞活力、侵袭和迁移能力，并促进细胞凋亡和细胞周期G2期阻滞^[4]。BAY-598（10μM）处理结直肠癌HCT 116和LoVo细胞48小时，显著抑制SMYD2的甲基转移酶活性，降低HNRNPK蛋白K422位点的单甲基化水平，从而减弱HNRNPK与EGFL7 mRNA的结合能力^[5]。

在体内，BAY-598（5mg/kg）每隔一日腹腔注射，联合多柔比星（2mg/kg）每五日腹腔注射，用于处理荷A549细胞异种移植瘤的雌性裸鼠，持续32天。BAY-598与多柔比星联合给药显著抑制了非小细胞肺癌异种移植瘤的生长^[4]。BAY-598（50mg/kg）每日腹腔注射，联合阿帕替尼（30mg/kg）每日口服灌胃，用于处理结直肠癌患者来源异种移植（PDX）模型的裸鼠连续14天，BAY-598显著抑制了结直肠癌移植瘤的血管生成^[5]。