PVTX-405 is a selective oral IKZF2 molecular glue degrader with a DC50 of 0.7 nM and a maximum degradation (Dmax) of 91%. It enhances degradation efficiency, significantly reduces off-target degradation, and minimizes hERG inhibition with an IC50 of 48 µM. PVTX-405 effectively inhibits MC38 tumor growth in Crbn391VC57BL/6 mouse xenograft models and shows superior synergistic anticancer effects when combined with immune checkpoint therapies (ICTs) such as anti-PD1 or anti-LAG3 antibodies.

IZKF2:0.7 nM (DC50)

PVTX-405 (Compound 16a) exhibits exceptional substrate selectivity, minimally affecting IKZF1, IKZF3, GSPT1, and CK1α protein levels even at concentrations up to 10 µM with a D max of less than 20%. In Jurkat cells, PVTX-405 (0.01-10000 nM, 1-6 hours) degrades IKZF2 in a CRBN-dependent manner, achieving a DC 50 of 6.3 nM and a D max of 65%, with maximum degradation occurring within 3 hours. At concentrations of 1-1000 nM over 24 hours, PVTX-405 effectively modulates established IKZF2 transcription targets, increasing the inflammatory cytokine IL-2 and reducing the suppressive activity of Tregs, thus promoting Teff cell proliferation in Jurkat T cells. Additionally, PVTX-405 (0.1-1000 nM, 3-6 hours) induces dose-dependent degradation of IKZF2, disrupts the stability of human Treg cells, and triggers the proliferation of Teff cells.

PVTX-405 (Compound 16a), administered orally at 30 mg/kg once daily for 21 days, significantly inhibits the growth of MC38 tumors in the Crbn 391V C57BL/6 mouse-derived MC38 tumor xenograft model. Additionally, when used in combination with anti-PD1 or anti-LAG3 antibodies, it enhances survival rates in mice.