HDAC6 inhibitors(Newland Pharmaceutical)

Histone deacetylase 6 (HDAC6) has emerged as a promising therapeutic target in drug discovery. Aberrant expression of HDAC6 is associated with various diseases, including cancer, neurodegenerative disorders, and pathological autoimmune responses. Inhibition of HDAC6 has been extensively investigated for the treatment of multiple diseases, particularly cancer. A variety of HDAC6 inhibitors have been developed and are at different stages of drug development. Currently, diverse strategies targeting HDAC6 are being explored, such as isoform selective inhibitors, multi-targeted inhibitors and PROTACs. This review summarizes the functions of HDAC6, its roles in different disorders, and various types of modulators targeting HDAC6. These insights may provide valuable information for further design of therapeutic drugs by targeting HDAC6.

Triple-negative breast cancer (TNBC) is an aggressive subtype characterized by limited treatment options. PANoptosis, a newly identified programmed cell death pathway, offers therapeutic strategies for TNBC. ACY-1215 has demonstrated preliminary efficacy in patients with TNBC and HR⁺/HER2^- metastatic breast cancer. However, its moderate target engagement and suboptimal selectivity may limit its clinical efficacy. In this study, a series of potent HDAC6-selective inhibitors bearing a 5-pyrazolyl-benzotriazole scaffold has been developed. Compound TNI-97 demonstrated potent HDAC6 inhibitory activity and great isoform selectivity. TNI-97 elicited PANoptotic cell death in MDA-MB-453 cell models in vitro and in vivo. 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.