Discovery of epigenetic modulators targeting HDACs and EZH2 simultaneously for the treatment of hematological...

Area of Science:

• Oncology
• Medicinal Chemistry
• Epigenetics

Background:

• Epigenetic-targeted therapy is crucial for cancer treatment.
• Co-targeting histone deacetylases (HDACs) and enhancer of zeste homolog 2 (EZH2) shows synergistic antitumor effects in hematological malignancies.

Purpose of the Study:

• To design, synthesize, and evaluate novel tazemetostat-based dual inhibitors of HDACs and EZH2.
• To assess the antiproliferative, differentiation-inducing, and apoptosis-inducing activities of these novel compounds in cancer cell lines.

Main Methods:

• Rational design and synthesis of novel HDACs/EZH2 dual inhibitors.
• Biological evaluation of antiproliferative activity against diffuse large-cell B cell lymphomas (DLBCL) and acute myeloid leukemia (AML) cell lines.
• Comparison of efficacy with approved drugs tazemetostat and SAHA.

Main Results:

• Compounds 22a and 22b identified as potent HDACs/EZH2 dual inhibitors.
• Compounds 22a and 22b exhibited robust antiproliferative activity against EZH2-mutant DLBCL and AML cell lines.
• In EZH2-mutant DLBCL, 22a and 22b showed superior short-term antiproliferative effects compared to tazemetostat and comparable/superior long-term effects to SAHA.
• In AML cells, 22a and 22b demonstrated potent antiproliferative, differentiation-inducing, and apoptosis-inducing abilities, outperforming tazemetostat and SAHA.
• Synergistic anti-AML effects were observed when combining dual inhibitors with other anti-AML drugs.

Conclusions:

• Novel HDACs/EZH2 dual inhibitors, exemplified by 22a and 22b, represent a promising therapeutic strategy for hematological malignancies.
• These compounds show significant potential in treating DLBCL with EZH2 mutations and AML.
• Combination therapy with these dual inhibitors may enhance anti-AML treatment outcomes.