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.

Treatment with BAS-2 leads to fumarate accumulation by 13C glucose labelling, along with downstream succination of proteins and cell death. Together, these results identify HDAC6 inhibition as a regulator of endogenous FH activity in tumour cells, and highlight it as a promising candidate for indirectly targeting tumour metabolism.

In conclusion, although additional in vitro and in vivo studies are required for the validation, in silico evaluation of ZINC27653366 may position it as a promising candidate for the treatment of different types of cancers.

The expression of autophagy-related proteins Atg7, Atg3, LC3B, and P62 was downregulated, and the expression of acetylated P53 protein was upregulated (P<0.05) . The HDAC6 inhibitor ACY-738 induces mitochondria-dependent apoptosis and autophagy in DLBCL cells by acetylating P53, thereby inhibiting DLBCL cell proliferation.

ACY-1215 has demonstrated preliminary efficacy in patients with TNBC and HR+/HER2- metastatic breast cancer. TNI-97 exhibited a TGI of 91% in MDA-MB-453 CDX as monotherapy and a TGI of 92% in 4T1 CDA when combined with paclitaxel. The discovery of TNI-97 holds promise for the development of more potent HDAC6 inhibitors as PANoptotic inducers and TNBC drug candidates.