HVH-2930

**HVH-2930** is a novel, orally active small molecule that functions as a **C-terminal inhibitor of Heat Shock Protein 90 (HSP90)**. It was rationally designed via structure-activity relationship studies as an indazole surrogate, structurally distinct from other C-terminal HSP90 inhibitors. HVH-2930 binds the ATP-binding pocket at the interface of the HSP90 homodimer's C-terminal domain, stabilizing the open conformation and hindering ATP binding, thereby inhibiting the chaperone function of HSP90. This mechanism leads to **suppression of the HER2 signaling pathway** by downregulating HER2 and its family members, disrupting their heterodimerization, and degrading HSP90 client proteins. HVH-2930 potently induces apoptosis and inhibits tumor growth and angiogenesis in trastuzumab-resistant HER2-positive breast cancer models without inducing the heat shock response—a principal drawback of earlier N-terminal HSP90 inhibitors. It also reduces cancer stem cell-like properties and shows synergistic activity when combined with paclitaxel. The compound is being developed primarily as a strategy to overcome **trastuzumab resistance in HER2-positive breast cancer**, with possible applications in other HER2-overexpressing malignancies such as gastric and esophageal cancer[1][2][4][6][8][9][10].