PI3K-Akt-mTOR pathway is a highly activated signal transduction pathway in human hematological malignancies and has been validated as a promising target for acute myeloid leukemia (AML) therapy. Herein, we designed and synthesized a series of 7-azaindazole derivatives as potent PI3K/mTOR dual inhibitors based on our previously reported FD223. Among them, compound FD274 showed excellent dual PI3K/mTOR inhibitory activity, with IC₅₀ values against PI3Kα/β/γ/δ and mTOR of 0.65 nM, 1.57 nM, 0.65 nM, 0.42 nM, and 2.03 nM, respectively, superior to compound FD223. Compared to the positive drug Dactolisib, FD274 exhibited significant anti-proliferation of AML cell lines (HL-60 and MOLM-16 with IC₅₀ values of 0.092 μM and 0.084 μM, respectively) in vitro. Furthermore, FD274 demonstrated dose-dependent inhibition of tumor growth in the HL-60 xenograft model in vivo, with 91% inhibition of tumor growth at an intraperitoneal injection dose of 10 mg/kg and no observable toxicity. All of these results suggest that FD274 has potential for further development as a promising PI3K/mTOR targeted anti-AML drug candidate.

PI3K-Akt-mTOR 通路是人类血液恶性肿瘤中高度激活的信号转导通路，已被验证为急性髓系白血病 (AML) 治疗的有希望的靶点。在此，我们基于之前报道的FD223，设计并合成了一系列7-氮杂吲唑衍生物作为有效的PI3K/mTOR双重抑制剂。其中，化合物FD274表现出优异的PI3K/mTOR双重抑制活性，对PI3Kα/β/γ/ δ和mTOR的IC _50值分别为0.65 nM、1.57 nM、0.65 nM、0.42 nM和2.03 nM，优于化合物FD274。 FD223。与阳性药物Dactolisib相比，FD274在体外对AML细胞系（HL-60和MOLM-16，IC ₅₀值分别为0.092 μM和0.084 μM）表现出显着的抗增殖作用。此外，FD274在体内HL-60异种移植模型中表现出剂量依赖性的肿瘤生长抑制作用，腹腔注射剂量为10 mg/kg时，肿瘤生长抑制率达到91%，并且没有可观察到的毒性。所有这些结果表明，FD274作为一种有前途的 PI3K/mTOR 靶向抗 AML 候选药物具有进一步开发的潜力。