Discovery ofaNovel Series of iso -Indolinone-Based Glutarimidesas Highly Efficacious and SelectiveIKZF2 Molecular Glue Degraders

Abstract Immunosuppressive Tregs, regulated by IKZF2 (Helios), promote tumor immune evasion and resistance to immune checkpoint therapies (ICTs). Targeting IKZF2 degradation offers a promising cancer immunotherapy approach. We developed a novel series of iso-indolinone-based glutarimides, identifying compound 55 as a potent, selective IKZF2 degrader with >90% Dmax in Jurkat cells, outperforming benchmarks DKY709 and PVTX-405. It exhibits strong selectivity over IMiD neo-substrates, favorable solubility, metabolic stability, and oral bioavailability in rodents. PK/PD studies confirmed profound, persistent IKZF2 degradation in mouse spleen and thymus after a single oral dose. As a promising early-stage tool, 55 provides a foundation for further preclinical evaluation in cancer immunotherapy.