1. Academic Validation
  2. Multitargeting HDAC Inhibitors Containing a RAS/RAF Protein Interfering Unit

Multitargeting HDAC Inhibitors Containing a RAS/RAF Protein Interfering Unit

  • J Med Chem. 2024 Feb 8;67(3):2066-2082. doi: 10.1021/acs.jmedchem.3c01941.
Yuanjiang Wang 1 2 Jianluo Zhang 1 Kun Li 1 Shengjin Xia 1 Shaohua Gou 1 2
Affiliations

Affiliations

  • 1 Pharmaceutical Research Center and School of Chemistry and Chemical Engineering, Southeast University, Nanjing 211189, PR China.
  • 2 Jiangsu Province Hi-Tech Key Laboratory for Biomedical Research, Southeast University, Nanjing 211189, PR China.
Abstract

In this work, a series of multitargeting histone deacetylase (HDAC) inhibitors capable of regulating the signal transduction between Ras protein and downstream effectors were obtained by introducing a zinc-ion-binding group into the framework of rigosertib via different linkers. Among them, two representative compounds, XSJ-7 and XSJ-10, not only showed stronger antiproliferative activity against many types of Cancer cells including solid tumor cells but also presented more potent inhibition on different subtypes of HDAC than suberoylanilide hydroxamic acid (SAHA). Significantly, XSJ-10 presented moderate pharmacokinetic behaviors and showed stronger antitumor activity than oxaliplatin, SAHA, and rigosertib in the HT-29 xenograft mouse models without significant systemic toxicity. Research on the Anticancer mechanism of XSJ-10 revealed that it can effectively induce the Apoptosis of Cancer cells and suppress the tumor by strongly inhibiting the RAS-RAF-MEK-ERK signaling pathway and the acetylation level of HDAC3.

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Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-157740
    HDAC抑制剂