HPV E7-ZER1 inhibitor Compound 4 (ZER1-IN-1) is a first-in-class small-molecule inhibitor of ZER1 ARM-repeat domain, selectively blocks the ZER1-E7 interaction, leading to retinoblastoma (Rb) stabilization, inhibition of HPV-positive cervical cancer cell proliferation.
Compound 4 inhibitsHeLa cell growth with an IC50 of 23.05 μM, but with no sensitivity in ZER1 knockout HeLa cells, has minimal effects on the proliferation of HPV-negative C33A cells.
Compound 4 treatment effectively inhibited cell growth of the HPV18-positive SUNE2 cell line but not the HPV-negative SCC-9 cells.
Compound 4 significantly reduced tumor volume and weight in mice bearing subcutaneous xenografts of either HPV18-positive HeLa.
HPV E7 is the recruitment of the CRL2ZER1 ubiquitin ligase complex to target Rb for proteasomal degradation.
ZER1 functions as the substrate receptor within the Cullin-2-RING E3 ligase (CRL2), and this E7-ZER1-dependent inactivation of Rb is essential for HPV-driven transformation.