rocilinostat (ACY-1215)

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.

We investigated the impact of various classes of histone deacetylase inhibitors (HDACi) (i.e. broad-spectrum HDACi (vorinostat), class I HDACi (entinostat), preferential class IIb HDAC6i (ricolinostat) and dual HDAC class I/IIb inhibitors (HDAC1/6i)) on mechanisms of the DDR using parental (J82WT) and cisplatin (CisPt)-resistant bladder carcinoma cells (J82CisR). This is due to amplification of replicative and transcriptional stress caused by CisPt treatment as well as interference with DDR mechanisms and DNA repair, eventually promoting apoptosis. Thus, epigenetic targeting of DDR-related death pathways by class I HDACi is useful to overcome acquired CisPt resistance of tumor cells.

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.

These findings demonstrate that ACY-1215 mitigates neuropathic pain by modulating STAT3 acetylation/phosphorylation and suppressing HDAC6/STAT3-driven CCL7 and cytokine release. This study underscores the role of the HDAC6/STAT3/CCL7 signaling axis in neuropathic pain and highlights the therapeutic potential of HDAC6 inhibitors for pain management.

HDAC6 selective inhibitor ACY-1215 inhibited the NF-κB signaling pathway. VHL attenuated arecoline-induced OSF by inhibiting the ubiquitination of HDAC6 and blocking NF-κB pathway. As a result, our study offers new perspectives into the discovery of novel tactics that can be employed against OSF.

In this study, we developed tumor microenvironment-responsive nanoparticles (GdNPs) to enhance SDT effectiveness through epigenetic reprogramming of the TME by encapsulating the sonosensitizer chlorin e6 (Ce6) and the histone deacetylase 6 (HDAC6) inhibitor Ricolinostat (Ric) (GdNPs/Ce6-Ric)...Furthermore, GdNPs/Ce6-Ric minimized lung metastases by not only improving systemic immune responses but also inhibiting TGFβ-induced epithelial-mesenchymal transition (EMT) of tumor cells through the blockade of α-tubulin deacetylation. Thus, GdNPs/Ce6-Ric-based epigenetic modulation of the immunosuppressive TME offers a promising approach to enhance the efficacy of SDT in treating TNBC.

In summary, ACY1215 can inhibit the NF-κB and STAT3 signaling pathways in astrocytes, reduce inflammation and ameliorate SCI. Our results provide a novel strategy for the treatment of SCI.

P1/2, N=23, Terminated, Jennifer Amengual | Completed --> Terminated; Lack of funding

P1/2, N=103, Terminated, Celgene | Active, not recruiting --> Terminated; Lack of efficacy

ACY-1215 has a protective effect on the cellular model of NAFLD induced by fatty acids and lipopolysaccharide, as well as the C57BL/6J mouse model induced by a high-fat diet. ACY-1215 may play a protective role by inhibiting CD14/TLR4/MyD88/MAPK/NFκB signal pathway.

P1, N=3, Active, not recruiting, Dana-Farber Cancer Institute | Trial completion date: Apr 2026 --> Apr 2027 | Trial primary completion date: Apr 2024 --> Apr 2026

Fab' fragments from Obinutuzumab (OBN) and Isatuximab (ISA) were employed in the synthesis of anti-CD20 (Fab'OBN-MORF1) and anti-CD38 (Fab'ISA-MORF1) bispecific engagers...Pretreatment of patient cells with gemcitabine or ricolinostat markedly increased cell surface CD20 and CD38 expression, respectively...Our findings demonstrate DFMT's potential in personalized CLL therapy. Further research is needed to validate these outcomes in a larger number of patient samples and to explore DFMT's applicability to other malignancies.