Discovery of SILA-123 as a Highly Potent FLT3 Inhibitor for the Treatment of Acute Myeloid Leukemia with Various FLT3 Mutations

  • J Med Chem. 2024 Sep 11. doi: 10.1021/acs.jmedchem.4c00529.
Tian-Hua Wei  1 ,  Zi-Xuan Wang  1 ,  Meng-Yi Lu  2 ,  Yu-Jing Xu  1 ,  Jin Yang  1 ,  Xing-Feng Ni  1 ,  Yang Cheng  1 ,  Meng-Yuan Zhang  1 ,  Jia-Chuan Liu  1 ,  Qing-Qing Li  1 ,  Jiao Cai  1 ,  Zi-Jun Chen  1 ,  Ji-Bo Kang  1 ,  Nan Li  1 ,  Wei-Chen Dai  1 ,  Ning Ding  1 ,  Yan-Cheng Yu  1 ,  Xue-Jiao Leng  1 ,  Xin Xue  1 ,  Xiao-Long Wang  1 ,  Shan-Liang Sun  1 ,  Ye Yang  3 ,  Nian-Guang Li  1 ,  Zhi-Hao Shi  4
Affiliations
  • 1. National and Local Collaborative Engineering Center of Chinese Medicinal Resources Industrialization and Formulae Innovative Medicine, Nanjing University of Chinese Medicine, 138 Xianlin Road, Nanjing, Jiangsu 210023, China.
  • 2. Department of Biostatistics, School of Public Health, Nanjing Medical University, 101 Longmian Avenue, Nanjing, Jiangsu 211166, China.
  • 3. School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China.
  • 4. Laboratory of Molecular Design and Drug Discovery, School of Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, Jiangsu 211198, China.
PMID: 39258312 DOI: 10.1021/acs.jmedchem.4c00529
Abstract

The FLT3-ITD (internal tandem duplication) mutant has been a promising target for acute myeloid leukemia (AML) drug discovery but is now facing the challenge of resistance due to point mutations. Herein, we have discovered a type II FLT3 Inhibitor, SILA-123. This inhibitor has shown highly potent inhibitory effects against FLT3-WT (IC50 = 2.1 nM) and FLT3-ITD (IC50 = 1.0 nM), tumor cells with the FLT3-ITD mutant such as MOLM-13 (IC50 = 0.98 nM) and MV4-11 (IC50 = 0.19 nM), as well as BaF3 cells associated with the FLT3-ITD mutant and point mutations like BaF3-FLT3-ITD-G697R (IC50 = 3.0 nM). Moreover, SILA-123 exhibited promising kinome selectivity against 310 kinases (S score (10) = 0.06). In in vivo studies, SILA-123 significantly suppressed the tumor growth in MV4-11 (50 mg/kg/d, TGI = 87.3%) and BaF3-FLT3-ITD-G697R (50 mg/kg/d, TGI = 60.0%) cell-inoculated allograft models. Our data suggested that SILA-123 might be a promising drug candidate for FLT3-ITD-positive AML.

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