P1, N=57, Completed, AnnJi Pharmaceutical Co., Ltd. | Recruiting --> Completed

This hypothesis was confirmed by SREBP-1 silencing, which also potentiated the antitumor efficacy of the ITF3756/BTZ combination in HCT116 cells. Overall, these results reveal a particular antitumor efficacy of the selective HDAC6 inhibitor in combination with BTZ in colon cancer cells and suggest that inhibiting lipogenesis is a useful tool to further increase the synergistic effectiveness.

10g also showed superior metabolic stability compared to ACY-1215 in a microsomal stability study. In summary, this work highlighted the therapeutic potential of aroylpyrrole-based sHDAC6 inhibitors and provided a valuable lead compound in treating cervical cancer.

P2, N=165, Recruiting, Novartis Pharmaceuticals | Not yet recruiting --> Recruiting

P2, N=165, Not yet recruiting, Novartis Pharmaceuticals

The HDI-3 emerged as the most promising candidate among replicate simulations, exhibiting a substantially favorable MM/GBSA binding free energy of -130.67 kcal/mol-indicative of strong thermodynamic stability and stronger binding affinity compared to reference inhibitors Trichostatin A and Ricolinostat. Therefore, experimental validation is essential to confirm the compound's efficacy and safety. This integrated computational pipeline provides an efficient strategy to accelerate targeted drug discovery, laying the groundwork for future experimental investigations.

Furthermore, in an HCT116 xenograft mouse model, compound 5b significantly inhibited tumor growth without affecting body weight. The combination of in vitro and in vivo studies provides robust evidence supporting the potential of compound 5b as a highly potent and selective HDAC6 inhibitor, possessing promising anti-proliferative and apoptosis-inducing properties for further preclinical development.

P1, N=19, Active, not recruiting, Massachusetts General Hospital | Trial completion date: Sep 2024 --> Sep 2026 | Trial primary completion date: Sep 2024 --> Sep 2025

Their activity was associated with HDAC6 inhibition below 2 nM, blockade of AKT2 phosphorylation at 2 μM, and synergistic reversal of venetoclax resistance in two cancer models. These findings validate our modeling approach for predicting hybrid inhibitors and highlight 6b and 6k as promising leads for hematological cancer therapy.

Mechanistically, ZNF295-AS1 functions as a competing endogenous RNA, sponging miR-762 and thus relieving the repression of HDAC6, ultimately influencing autophagy and tumor progression. In conclusion, ZNF295-AS1 is implicated in the regulation of autophagy and malignancy in NPC through the miR-762/HDAC6 axis, suggesting its potential as a novel diagnostic and therapeutic target in NPC management.

SIGNIFICANCE STATEMENT: Selective histone deacetylase 6 (HDAC6) inhibitors provide a safer alternative to nonselective HDAC inhibitors, with potential applications in cancer. This study identifies compound 6a as a promising lead with remarkable HDAC6 specificity, offering a foundation for developing targeted and efficient therapeutics.