NDNB-25

NDNB-25 is a novel, isoform-selective small molecule inhibitor of Heat Shock Protein 90 beta (Hsp90β). Developed through a structure-based approach, it is designed to overcome the limitations of traditional pan-Hsp90 inhibitors, which often induce a heat shock response that leads to chemoresistance and dose-limiting toxicities. In preclinical models of pancreatic ductal adenocarcinoma (PDAC), NDNB-25 has demonstrated the ability to reduce the expression of key oncogenic client proteins, including EGFR, IGF-1R, HER2, p-MEK, and c-Myc, without upregulating Hsp90 expression. The agent induces apoptosis, as evidenced by increased markers such as cleaved caspase-3 and cleaved PARP-1, and promotes epithelial differentiation. Preclinical studies show that NDNB-25 significantly inhibits tumor growth as a monotherapy and exhibits synergistic effects when combined with standard-of-care chemotherapy (nab-paclitaxel and gemcitabine), particularly in tumors with high Hsp90β expression.