DB1976 hydrochloride is a efficacious transcription factor PU.1 inhibitor. DB1976 dihydrochloride potently inhibits PU.1 binding (IC50 of 10 nM) and strongly inhibits the PU.1/DNA complex (with high DB1976-λB affinity, KD of 12 nM) in vitro. DB1976 dihydrochloride has apoptosis-inducing effect[1] [4].
DB1976 hydrochloride(0.1-100 mM，48h) led to decrease in the growth of PU.1 URE–/– AML cells (IC50: 105 μM); After DB1976(25uM,24h) treatment, PU.1 was lentivirally expressed in MOLM13 cells, and it was observed that the cytotoxic effects of the compound were rescued and cell viability was increased after treatment with DB1976[1].
DB1976 hydrochloride (5 mg/kg/day,28days)exposure decreased the interstitial, sub-epicardial and perivascular fibrosis induced by Ang-II in the atrial tissue[2]. DB1976 (5 mg/kg/day,28days)effectively attenuated Ang-II-induced increase in the number of atrial fibroblasts and reduced the expression of PCNA, α-SMA, SMemb, ED-A fibronectin, and DDR2 in vitro and in vivo[2]. In an asthma model, DB1976 (1 mg/kg and 2.5 mg/kg，5 days per week for 3 weeks) increased airway eosinophils and reduced small airway collagen deposition but had no effect on the number of mucus-secreting cells[3].
References:
[1]. Antony-Debré I, et al. Pharmacological inhibition of the transcription factor PU.1 in leukemia. J Clin Invest. 2017 Dec 1;127(12):4297-4313.
[2]. Hu J, et al. PU.1 inhibition attenuates atrial fibrosis and atrial fibrillation vulnerability induced by angiotensin-II by reducing TGF-β1/Smads pathway activation. J Cell Mol Med. 2021 Jul;25(14):6746-6759.
[3]. Tu, X., Gomez, H.M., Kim, R.Y. et al. Airway and parenchyma transcriptomics in a house dust mite model of experimental asthma. Respir Res 24, 32 (2023).
[4].Stephens DC, Kim HM, Kumar A, Farahat AA, Boykin DW, Poon GM. Pharmacologic efficacy of PU.1 inhibition by heterocyclic dications: a mechanistic analysis. Nucleic Acids Res. 2016 May 19;44(9):4005-13.
DB1976 hydrochloride是一种有效的转录因子 PU.1 抑制剂。DB1976 hydrochloride在体外可有效抑制 PU.1 结合（IC50 为 10 nM），并强烈抑制 PU.1/DNA 复合物（具有高 DB1976-λB 亲和力，KD 为 12 nM）。DB1976 hydrochloride具有诱导细胞凋亡的作用[1] [4]。
DB1976 hydrochloride(0.1-100 mM，48h)使PU.1 URE–/– AML细胞生长减少（IC50：105 μM）；DB1976(25 uM，24h)处理后，PU.1 URE–/– AML细胞出现凋亡（annexin-V+PI–）[1]。
DB1976 hydrochloride(5mg/kg/day，28天)暴露减少了心房组织中由血管紧张素Ⅱ诱导的间质、心外膜下和血管周围纤维化。DB1976 有效减少Ang-II诱导的心房成纤维细胞的数量增加，并降低体内和体外 PCNA、α-SMA、SMemb 和 ED-A 纤连蛋白和 DDR2 的表达[2]。在哮喘模型中，DB1976（1 mg/kg 和 2.5 mg/kg，每周 5 天，持续 3 周）增加了气道嗜酸性粒细胞，减少了小气道胶原沉积，但对粘液分泌细胞的数量没有影响l[3]。