Discovery of TNI-97 as a Highly Selective, Orally Bioavailable HDAC6 Inhibitor for the Treatment of Triple-Negative Breast Cancer

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.