Development of PVTX-405 as a potent and highly selective molecular glue degrader of IKZF2 for cancer immunotherapy.

ABSTRACT: IKZF2 (Helios) is a transcription factor that is selectively expressed by Tregs and is essential for preserving the function and stability of Tregs in the tumor microenvironment (TME), where it suppresses the anti-tumor immune response. Targeted IKZF2 degradation by small molecules represents a promising strategy for the development of a new class of cancer immunotherapy. Herein, we describe the discovery of PVTX-405, a potent, effective, highly selective, and orally efficacious IKZF2 molecular glue degrader. PVTX-405 degrades IKZF2 (DC₅₀ = 0.7 nM and D_max = 91%) while sparing other CRBN neo-substrates. Degradation of IKZF2 by PVTX-405 increases production of inflammatory cytokine IL-2 and reduces the suppressive activity of Tregs, leading to an increase in Teff cell

SUBMITTER: Chen Z 

PROVIDER: S-EPMC12046021 | biostudies-literature | 2025 May

REPOSITORIES: biostudies-literature