Zheng Xuan, Chen Zhiwen, Guo Ming, Liang Hong, Song Xiaojuan, Liu Yiling, Liao Zhenling, Zhang Yan, Guo Jing, Zhou Yang, Zhang Zhi-Min, Tu Zhengchao, Zhang Ye, Chen Yongheng, Zhang Zhang, Lu Xiaoyun
State Key Laboratory of Bioactive Molecules and Druggability Assessment, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education, Guangzhou City Key Laboratory of Precision Chemical Drug Development, School of Pharmacy, Jinan University, #855 Xingye Avenue, Guangzhou 510632, China.
Department of Oncology, NHC Key Laboratory of Cancer Proteomics, State Local Joint Engineering Laboratory for Anticancer Drugs, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
ACS Pharmacol Transl Sci. 2024 Apr 11;7(5):1485-1506. doi: 10.1021/acsptsci.4c00071. eCollection 2024 May 10.
Secondary mutations in Fms-like tyrosine kinase 3-tyrosine kinase domain (FLT3-TKD) (e.g., D835Y and F691L) have become a major on-target resistance mechanism of FLT3 inhibitors, which present a significant clinical challenge. To date, no effective drugs have been approved to simultaneously overcome clinical resistance caused by these two mutants. Thus, a series of pyrazinamide macrocyclic compounds were first designed and evaluated to overcome the secondary mutations of FLT3. The representative exhibited potent inhibitory activities against FLT3 and FLT3 with IC values of 1.5 and 9.7 nM, respectively. also strongly suppressed the proliferation against Ba/F3 cells transfected with FLT3-ITD, FLT3-ITD-D835Y, FLT3-ITD-F691L, FLT3-ITD-D835Y-F691L, and MV4-11 acute myeloid leukemia (AML) cell lines with IC values of 12.2, 10.5, 24.6, 16.9, and 6.8 nM, respectively. Furthermore, demonstrated ideal anticancer efficacy in a Ba/F3-FLT3-ITD-D835Y xenograft model. The results suggested that can serve as a promising macrocycle-based FLT3 inhibitor for the treatment of AML.
Fms样酪氨酸激酶3-酪氨酸激酶结构域（FLT3-TKD）的继发性突变（例如D835Y和F691L）已成为FLT3抑制剂的主要靶向耐药机制，这带来了重大的临床挑战。迄今为止，尚无有效药物被批准可同时克服由这两种突变体引起的临床耐药性。因此，首先设计并评估了一系列吡嗪酰胺大环化合物以克服FLT3的继发性突变。代表性化合物对FLT3和FLT3表现出强效抑制活性，其IC值分别为1.5和9.7 nM。该化合物还强烈抑制转染了FLT3-ITD、FLT3-ITD-D835Y、FLT3-ITD-F691L、FLT3-ITD-D835Y-F691L的Ba/F3细胞以及MV4-11急性髓系白血病（AML）细胞系的增殖，其IC值分别为12.2、10.5、24.6、16.9和6.8 nM。此外，该化合物在Ba/F3-FLT3-ITD-D835Y异种移植模型中显示出理想的抗癌疗效。结果表明，该化合物可作为一种有前景的基于大环的FLT3抑制剂用于治疗AML。
