Authors
Yingjie Chang, Xue Li, Huirui Wang, Huajun Zhao, Yue Zhou, Wenchao Bi, Ruixue Cheng, Yuxin Shi, He Weng, Xinying Yang, Wei Zhao, Hao Fang, Xuben Hou
Published in
Acta pharmaceutica Sinica. B. Volume 16. Issue 8. Pages 5383-5404. Epub May 26, 2026.
Abstract
Dual FLT3/HDAC inhibition represents a promising synergistic strategy to address tumor heterogeneity. Building upon our prior lead 25h, we developed novel 6-ethylpyrazine-2-carboxamide derivatives via systematic structural optimization to enhance pharmacokinetic properties and target selectivity. The optimized compound, CF-2-17, demonstrated potent dual inhibition of FLT3 (IC50 = 1.1 nmol/L) and HDACs (IC50 = 9.6 nmol/L), and exhibited a 27-fold selectivity for HDAC1 over HDAC6. Its improved physicochemical properties, including enhanced solubility and metabolic stability, translated into favorable plasma exposure in vivo. In the MOLM-13 (FLT3-ITD) xenograft model, oral administration of CF-2-17 showed antitumor efficacy comparable to combination therapy, without observable toxicity. CF-2-17 also exhibited antiproliferative activity against non-FLT3-ITD hematological malignancies and solid tumors, outperforming single-target agents. Furthermore, CF-2-17 effectively remodeled the tumor immune microenvironment through CD4+ T cell activation and IFN-γ elevation, achieving 87% tumor growth inhibition in LLC syngeneic models. Mechanistically, CF-2-17 reversed FLT3 blockade-induced DC dysfunction via activation of the NF-κB pathway, thereby reinstating DC-mediated antitumor immunity. This dual FLT3/HDAC inhibitor demonstrates synergistic epigenetic-immune modulation, offering a promising approach for heterogeneous malignancies.
PMID:
42592389
Bibliographic data and abstract were imported from PubMed on 14 Sep 2026.
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