Multitargeting HDAC Inhibitors Containing a RAS/RAF Protein Interfering Unit

Area of Science:

• Medicinal Chemistry
• Oncology
• Molecular Biology

Background:

• Histone deacetylase (HDAC) inhibitors are crucial in cancer therapy.
• Rigosertib targets the RAS signaling pathway, a key driver in many cancers.
• Developing multitargeting agents offers a promising strategy for enhanced efficacy.

Purpose of the Study:

• To design and synthesize novel multitargeting HDAC inhibitors.
• To investigate the antiproliferative and antitumor activities of these compounds.
• To elucidate the anticancer mechanisms, focusing on the RAS pathway and HDAC inhibition.

Main Methods:

• Synthesis of rigosertib analogs with zinc-binding groups.
• In vitro antiproliferative assays against various cancer cell lines.
• Inhibition assays against different HDAC subtypes.
• In vivo efficacy studies in HT-29 xenograft mouse models.
• Pharmacokinetic profiling and toxicity assessment.
• Western blot analysis to assess signaling pathway modulation.

Main Results:

• Two compounds, XSJ-7 and XSJ-10, exhibited significant antiproliferative effects.
• XSJ-10 demonstrated superior HDAC inhibition compared to SAHA.
• XSJ-10 showed enhanced antitumor activity and moderate pharmacokinetics in vivo.
• XSJ-10 effectively induced cancer cell apoptosis and suppressed tumor growth.
• Inhibition of the RAS-RAF-MEK-ERK pathway and HDAC3 acetylation was confirmed.

Conclusions:

• Novel rigosertib-based HDAC inhibitors (XSJ-7, XSJ-10) were developed.
• XSJ-10 displays potent anticancer activity through dual inhibition of HDAC and the RAS pathway.
• XSJ-10 represents a promising candidate for further preclinical and clinical development.