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

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Triple-negative breast cancer (TNBC) presents a significant clinical challenge due to limited targeted therapies.
• PANoptosis, a novel programmed cell death pathway, emerges as a promising therapeutic avenue for TNBC.
• Existing agents like ACY-1215 show potential but face limitations in target engagement and selectivity.

Purpose of the Study:

• To design and synthesize novel HDAC6-selective inhibitors for TNBC treatment.
• To evaluate the efficacy of these inhibitors in inducing PANoptosis and combating TNBC.
• To identify potent drug candidates for further clinical development.

Main Methods:

• Development of a 5-pyrazolyl-benzotriazole scaffold for HDAC6 inhibitors.
• In vitro and in vivo evaluation of compound TNI-97 in TNBC cell models (MDA-MB-453).
• Assessment of TNI-97's efficacy as monotherapy and in combination with paclitaxel in xenograft models (MDA-MB-453 CDX and 4T1 CDA).

Main Results:

• Compound TNI-97 demonstrated potent and selective HDAC6 inhibition.
• TNI-97 effectively induced PANoptosis in MDA-MB-453 cells.
• Significant tumor growth inhibition (TGI) was observed: 91% as monotherapy and 92% in combination therapy.

Conclusions:

• TNI-97 is a potent HDAC6 inhibitor that induces PANoptosis and shows significant preclinical efficacy against TNBC.
• The developed scaffold offers a promising platform for creating novel TNBC therapeutics.
• TNI-97 represents a potential drug candidate for advancing TNBC treatment strategies.