PVTX-405 is a potent, highly selective, rapid and orally efficacious CRBN-dependent glue degrader of IKZF2 with DC50 of 0.7 nM in IKZF2 HiBiT degradation assay in HEK293 cells, Dmax = 91%.
PVTX-405 binds to cereblon with IC50 of 99 nM and is five-fold tighter than DKY709 (NVP-DKY709, Cat#PC-20145), also is 2-fold more potent than DKY709 in inducing IKZF2 degradation.
PVTX-405 has much weaker hERG inhibition with IC50 of 48 µM and IC30 of 18 µM in a manual patch-clamp assay, compared to DKY709.
PVTX-405 shows minimal effect in reducing levels of IKZF1, IKZF3, GSPT1 and CK1α proteins with Dmax values of <20% at up 10 uM, and no effect on SALL4 (DC50>1000 nM).
PVTX-405 demonstrated potent IKZF2 degradation with DC50 of 6.3 nM and Dmax of 65% in Jurkat cells using FACS assay.
PVTX-405 (DC50 = 6 nM and Dmax = 92%) demonstrated more rapid and potent degradation of IKZF2 in human primary CD25-enriched FOXP3 + CD4 T cells in vitro as compared to DKY709 (DC50 = 12 nM and Dmax = 73%) after a 6 h treatment.
PVTX-405 effectively degrades IKZF2, destabilizes human Tregs ex vivo, and induces the proliferation of Teff cells.
PVTX-405 (30 mg/kg, oral gavage using 100% PEG200) demonstrated anti-cancer efficacy in the MC38 mouse tumor xenograft model in immune-competent CrbnI391V C57BL/6 mice, effectively induced IKZF2 depletion.