stat5-in-1

STAT5-IN-1 (STAT5 Inhibitor) 是STAT5的抑制剂，对 STAT5β 亚型的IC50值为 47 μM。

MK256是一种新型的CDK8抑制剂，通过抑制STAT通路显示出针对AML的强大抗肿瘤活性。MK256能引发分化和成熟，并抑制AML细胞系的增殖。此外，MK256不仅下调了磷酸化的STAT1(S727)和STAT5(S726)，还减少了AML细胞系中MCL-1和CCL2的mRNA表达。在MOLM-14异种移植模型中, MK256的效能得到了证实，观察到治疗后磷酸化STAT1(S727)和STAT5(S726)的抑制作用。MK256在MOLM-14异种移植模型中的药理动力学研究显示了对STAT通路的剂量依赖性抑制效果。无论是体外还是体内研究都表明，MK256能有效地下调STAT通路。

AC-4-130, a powerful inhibitor of the SH2 domain of STAT5, effectively hinders STAT5 activation, dimerization, nuclear translocation, and transcription of genes reliant on STAT5. This compound directly binds to STAT5, ultimately leading to cell cycle arrest and apoptosis in FLT3-ITD-driven leukemic cells. AC-4-130 exhibits notable anti-cancer properties and effectively suppresses abnormal STAT5 activity in acute myeloid leukemia (AML), making it a promising therapeutic option [1].

CAY10763 is a dual inhibitor of indolamine 2,3-dioxygenase 1 (IDO1; IC50= 46 nM) and STAT3 activation.1It binds to STAT3 (Kd= 530 nM) and selectively reduces the levels of STAT3 phosphorylated at the tyrosine in position 705 (STAT3Y705) over phosphorylated STAT3S727, STAT1, and STAT5 in SKOV3 cells when used at a concentration of 500 nM. It also inhibits STAT3 nuclear translocation in SKOV3 cells. CAY10763 is cytotoxic to HCT116, SKOV3, A549, and HepG2 cancer cells (IC50s = 37, 28, 33, and 12 nM, respectively). It reduces tumor growth in B16 F10 mouse melanoma and HepG2 mouse xenograft models when administered at doses of 100 and 10 mg kg, respectively. 1.Huang, R., Jing, X., Huang, X., et al.Bifunctional naphthoquinone aromatic amide-oxime derivatives exert combined immunotherapeutic and antitumor effects through simultaneous targeting of indoleamine-2,3-dioxygenase and signal transducer and activator of transcription 3J. Med. Chem.63(4)1544-1563(2020)

BPR1J-340 is a potent and selective FLT3 inhibitor with potential anticancer activity. BPR1J-340 was identified as a novel potent FLT3 inhibitor by biochemical kinase activity (IC50 approximately 25 nM) and cellular proliferation (GC50 approximately 5 nM) assays. BPR1J-340 inhibited the phosphorylation of FLT3 and STAT5 and triggered apoptosis in FLT3-ITD(+) AML cells. The pharmacokinetic parameters of BPR1J-340 in rats were determined. BPR1J-340 also demonstrated pronounced tumor growth inhibition and regression in FLT3-ITD(+) AML murine xenograft models. The combination treatment of the HDAC inhibitor vorinostat (SAHA) with BPR1J-340 synergistically induced apoptosis via Mcl-1 down-regulation in MOLM-13 AML cells, indicating that the combination of selective FLT3 kinase inhibitors and HDAC inhibitors could exhibit clinical benefit in AML therapy.

JAK-IN-24 是一种 JAK 抑制剂，在 4 μM 或 1 mM ATP 存在时，IC50分别为 0.534 和 24 nM。JAK-IN-24 还抑制 PBMCIL-15诱导的 STAT5磷酸化，IC50为 86.171 nM。

PF15是一种将FLT3 kinase配体与CRBN配体结合的PROTAC，它是FLT3-ITD的高选择性降解剂，显示出76.7 nM的DC50。该化合物能有效抑制FLT3-ITD阳性细胞增殖，并降低FLT3和STAT5的磷酸化水平。在小鼠模型中，PF15也能够抑制肿瘤生长，对白血病研究具有潜在应用价值。

AK-2292 是一种有效和选择性STAT5PROTAC 降解剂，DC50值为 0.10 μM。AK-2292 在体外和体内诱导 STAT5A B 蛋白的降解。AK-2292 可在急性髓性白血病和慢性髓性白血病异种移植小鼠模型中诱导肿瘤消退。

PF15 TFA是一种连接FLT3 kinase配体和CRBN配体的PROTAC，作为FLT3-ITD的高选择性降解剂，DC50值为76.7 nM。该化合物可显著抑制FLT3-ITD阳性细胞增殖，并降低FLT3和STAT5磷酸化水平。PF15 TFA亦能抑制小鼠模型的肿瘤生长，并可用于白血病研究。

JAK2-IN-9（Compound A8）是一款选择性JAK2抑制剂（IC50：5 nM），能够抑制JAK2、STAT3和STAT5的磷酸化，并显示出代谢稳定性。此外，JAK2-IN-9能够诱导细胞凋亡（apoptosis），适用于骨髓增生性肿瘤（MPN）的研究。