ZJU-ENS Joint Laboratory of Medicinal Chemistry, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, P.R. China.
School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210023, P.R. China.
J Med Chem. 2023 Sep 14;66(17):11792-11814. doi: 10.1021/acs.jmedchem.3c00245. Epub 2023 Aug 16.
FLT3 inhibitors as single agents have limited effects because of acquired and adaptive resistance and the cardiotoxicity related to human ether-a-go-go-related gene (hERG) channel blockade further impedes safe drugs to the market. Inhibitors having potential to overcome resistance and reduce hERG affinity are highly demanded. Here, we reported a dual FLT3/CHK1 inhibitor , which displayed potencies to overcome varying acquired resistance in BaF3 cells with FLT3-TKD and FLT3-ITD-TKD mutations. Moreover, displayed high selectivity over c-KIT more than 1700-fold and greatly reduced hERG affinity, with an IC value of 58.4 μM. Further mechanistic studies demonstrated can upregulate p53 and abolish the outgrowth of adaptive resistant cells. In the in vivo studies, demonstrated favorable PK profiles and good safety, suppressed the tumor growth in the MV-4-11 cell inoculated mouse xenograft model, and prolonged the survival in the Molm-13 transplantation model, supporting its further development.
FLT3 抑制剂作为单一药物的疗效有限，因为存在获得性和适应性耐药性，并且与人 hERG 相关基因（hERG）通道阻滞相关的心脏毒性进一步阻碍了安全药物进入市场。因此，人们迫切需要具有克服耐药性和降低 hERG 亲和力潜力的抑制剂。在这里，我们报道了一种双重 FLT3/CHK1 抑制剂，它在具有 FLT3-TKD 和 FLT3-ITD-TKD 突变的 BaF3 细胞中显示出克服不同获得性耐药的潜力。此外，与 c-KIT 的选择性超过 1700 倍，大大降低了 hERG 亲和力，IC 值为 58.4 μM。进一步的机制研究表明，该化合物可以上调 p53 并消除适应性耐药细胞的生长。在体内研究中，显示出良好的 PK 特征和安全性，抑制 MV-4-11 细胞接种的小鼠异种移植模型中的肿瘤生长，并延长 Molm-13 移植模型中的存活时间，支持其进一步发展。
