BAY 2416964 is a potent and orally active inhibitor targeting aryl hydrocarbon receptor (AhR) with IC50 value of 341nM[1]. BAY 24169649 has been widely used in anti-cancer research[2].
In vitro, BAY 2416964 strongly inhibited the expression of CYP1A1 induced by AhR in human monocyte U937 cells with IC50 value of 21nM after treatment for 4h[3]. After treatment with 10nM BAY 2416964 for 24 hours, the expression of IL-10 in Tet2-deficient B cells was significantly inhibited[4]. Treatment with 100nM BAY 2416964 for 24 hours could significantly inhibit the expression of fibrotic factors (Fn, Col1a1 and α-SMA) induced by l-Kynurenine (100μM; 24h) and alleviate the fibrotic process in TCMK-1 cells[5]. BAY 2416964 treatment (20µM; 48h) increased the expression of type I interferon and raised the levels of IFNB1, CXCL10 and CCL5 in MDA-MB-436 cells[6].
In vivo, BAY 2416964 (20mg/kg/day; i.p.) treatment for one week can inhibit the expression of EZH2 caused by cisplatin (20mg/kg/day; i.p.) in the kidneys of C57BL/6 J mice, and alleviate cisplatin-induced renal dysfunction and tubular injury[7]. Treatment with BAY 2416964 (p.o.) at a dose of 30mg/kg/day for half a month enhanced the production of IFN-γ and increased the frequency of immune-stimulated tumor-infiltrating CD8+ T cells and natural killer (NK) cells, inhibited tumor growth in the melanoma mouse model[3].
References:
[1] Gutcher I, Schmees N, Röse L, et al. 2-Heteroaryl-3-oxo-2, 3-dihydropyridazine-4-carboxamides for the treatment of cancer: U.S. Patent 11,795,164[P]. 2023-10-24.
[2] Cohen Z, Petrenko E, Barisaac A S, et al. SLAYER: A Computational Framework for Identifying Synthetic Lethal Interactions through Integrated Analysis of Cancer Dependencies[J]. bioRxiv, 2024: 2024.05. 01.592073.
[3] Kober C, Roewe J, Schmees N, et al. Targeting the aryl hydrocarbon receptor (AhR) with BAY 2416964: a selective small molecule inhibitor for cancer immunotherapy[J]. Journal for Immunotherapy of Cancer, 2023, 11(11): e007495.
[4] Lu Z, Liu R, Wang Y, et al. Ten‐eleven translocation‐2 inactivation restrains IL‐10‐producing regulatory B cells to enable antitumor immunity in hepatocellular carcinoma[J]. Hepatology, 2023, 77(3): 745-759.
[5] Ren Q, Cheng L, Guo F, et al. Fisetin improves hyperuricemia-induced chronic kidney disease via regulating gut microbiota-mediated tryptophan metabolism and aryl hydrocarbon receptor activation[J]. Journal of Agricultural and Food Chemistry, 2021, 69(37): 10932-10942.
[6] Martin J C, da Silva Fernandes T, Chaudhry K A, et al. Aryl hydrocarbon receptor suppresses STING-mediated type I IFN expression in triple-negative breast cancer[J]. Scientific Reports, 2024, 14(1): 5731.
[7] Wen L, Ren Q, Guo F, et al. Tubular aryl hydratocarbon receptor upregulates EZH2 to promote cellular senescence in cisplatin-induced acute kidney injury[J]. Cell Death & Disease, 2023, 14(1): 18.
BAY 2416964是一种强效且具有口服活性的芳烃受体（AhR）抑制剂，IC50值为341nM[1]。BAY 2416964已被广泛应用于抗癌研究领域[2]。
在体外，BAY 2416964处理4小时后能显著抑制人单核细胞U937中AhR诱导的CYP1A1表达（IC50值为21nM）[3]。使用10nM BAY 2416964处理24小时可明显抑制Tet2缺陷型B细胞中IL-10的表达[4]。在TCMK-1细胞中，100nM的BAY 2416964处理24小时能显著抑制L-犬尿氨酸（100μM；24小时）诱导的纤维化因子（Fn、Col1a1和α-SMA）表达，缓解纤维化进程[5]。MDA-MB-436细胞经BAY 2416964（20µM；48小时）处理后，I型干扰素表达增加，IFNB1、CXCL10和CCL5水平升高[6]。
在体内，C57BL/6J小鼠连续一周腹腔注射BAY 2416964（20mg/kg/day）可抑制顺铂（20mg/kg/day；腹腔注射）引起的肾脏EZH2表达，改善顺铂诱导的肾功能障碍和肾小管损伤[7]。在黑色素瘤小鼠模型中，口服BAY 2416964（30mg/kg/day）处理半个月能促进IFN-γ生成，增加肿瘤浸润CD8+T细胞和自然杀伤（NK）细胞的频率，并抑制肿瘤生长[3]。