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Optimizing pyrazine-2-carboxamide derivatives as dual FLT3/HDAC inhibitors with enhanced pharmacokinetics and

Yingjie Chang1, Xue Li1, Huirui Wang1

  • 1Department of Medicinal Chemistry, State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Shandong Key Laboratory of Druggability Optimization and Evaluation for Lead Compounds, Shandong Basic Science Special Academic Zone (Pharmacy), School of Pharmaceutical Sciences, Cheelo College of Medicine, Shandong University, Jinan 250012, China.

Acta Pharmaceutica Sinica. B
|August 13, 2026
PubMed

Insights

A novel dual FLT3/HDAC inhibitor, CF-2-17, shows potent antitumor activity and favorable pharmacokinetics. This compound effectively modulates the tumor immune microenvironment, offering a promising strategy for treating heterogeneous malignancies.

Area of Science:

  • Oncology
  • Pharmacology
  • Immunology

Background:

  • Tumor heterogeneity poses a significant challenge in cancer treatment.
  • Dual inhibition of FLT3 and HDACs is a promising strategy to overcome resistance.
  • Prior lead compound 25h provided a foundation for further optimization.

Purpose of the Study:

  • To develop novel 6-ethylpyrazine-2-carboxamide derivatives with enhanced pharmacokinetic properties and target selectivity.
  • To evaluate the dual FLT3/HDAC inhibitory activity and antitumor efficacy of the optimized compound, CF-2-17.
  • To investigate the immunomodulatory effects and underlying mechanisms of CF-2-17.

Main Methods:

  • Systematic structural optimization of 6-ethylpyrazine-2-carboxamide derivatives.
  • In vitro assessment of FLT3 and HDAC inhibition (IC50 values) and selectivity.
  • In vivo evaluation in MOLM-13 xenograft and LLC syngeneic models.
  • Analysis of tumor immune microenvironment modulation, including T cell activation and cytokine production.
  • Mechanistic studies involving DC function and NF-κB pathway activation.

Main Results:

  • CF-2-17 demonstrated potent dual inhibition of FLT3 (IC50 = 1.1 nmol/L) and HDACs (IC50 = 9.6 nmol/L) with 27-fold selectivity for HDAC1 over HDAC6.
  • Improved physicochemical properties, solubility, and metabolic stability led to favorable in vivo plasma exposure.
  • Oral administration of CF-2-17 showed comparable antitumor efficacy to combination therapy in MOLM-13 xenografts without toxicity.
  • CF-2-17 exhibited broad antiproliferative activity against various hematological malignancies and solid tumors.
  • Significant tumor growth inhibition (87%) in LLC models via CD4+ T cell activation and IFN-γ elevation.
  • CF-2-17 reversed FLT3 blockade-induced DC dysfunction by activating the NF-κB pathway, restoring DC-mediated antitumor immunity.

Conclusions:

  • CF-2-17 is a potent dual FLT3/HDAC inhibitor with superior pharmacokinetic properties and broad-spectrum antitumor activity.
  • The compound effectively remodels the tumor immune microenvironment, suggesting a synergistic epigenetic-immune modulation mechanism.
  • CF-2-17 represents a promising therapeutic candidate for treating heterogeneous malignancies by targeting both cancer cells and the immune system.
Keywords:
Cancer immunotherapyFLT3HDACInhibitor

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