HVH-2930 is a specfiic small molecule C-terminal HSP90 inhibitor with SPR KD of 97.2 uM (HSP90α), reduces cell viability and induces apoptosis in HER2-positive breast cancer cells, targets the C-terminal HSP90 without inducing heat shock response (HSR).
HVH-2930 effectively inhibited the activity of C-terminal HSP90 by competitively interfering with the binding capability of the co-chaperone PPID, similar to the well-characterized C-terminal HSP90 inhibitor novobiocin.
HVH-2930 dose-dependently reduces cell viability in both trastuzumab-sensitive [BT474 and SKBR3] and -resistant cells [JIMT-1 and MDA-MB453] with IC50 of 6.86 μM, 5.13 μM, 3.94 and 3.93 μM, respectively.
HVH-2930 shows much more higher affinity than novobiocin.
HVH-2930 is a potent C-terminal hHSP90 inhibitor because it not only inhibits the binding of ATP but also stabilizes its open conformation.
HVH-2930-induced apoptosis is accompanied by activation of effector caspases and mitochondrial dysfunction.
HVH-2930 suppresses the HER2 signaling pathway by degrading HSP90 clients.
HVH-2930 inhibits tumor growth of trastuzumab-resistant JIMT-1 xenografts, attenuates CSC-like properties in HER2-positive breast cancer cells.