PVTX-321 is a potent and orally bioavailable estrogen receptor α (ERα) heterobifunctional degrader with DC50 of 0.15 nM, Dmax = 81% in MCF7 cells.
PVTX-321 demonstrates no significant degradation of GSPT1, CK1α, IKZF1, IKZF3, and SALL4 even at concentrations up to 10 μM, except for IKZF2 (DC50=34 nM and a Dmax of 57%).
PVTX-321 shows antiproliferative activity (gIC50 = 2.7 nM) in MCF-7 cells, exertsa similar inhibitory effect on cell growth for all 3 ER-positive breast cancer cell lines (gIC50: 0.6 nM T47D, 2.4 nM MCF-7, and 1.1 nM CAMA1).
PVTX-321 effectively induces rapid ER destruction in the presence of estradiol through CRL4-CRBN and a proteasome-dependent mechanism.
PVTX-321 suppresses cell proliferation in ER-positive breast cancer cells by degrading ER and inhibiting its transcriptional activity.
PVTX-321 effectively mediated the degradation of the three most prevalent clinically occurring ER point mutations (Y537S, D538G, or Q380E) and inhibits the proliferation of cells driven by these mutations.
PVTX-321 exhibited significant and dose-dependent reductions in ERα levels within the tumors across four dose levels (1 mg/kg, 3 mg/kg, 10 mg/kg, and 30 mg/kg) in wild-type MCF-7 xenograft mouse model.