Discovery of a Novel Series of <i>iso</i>-Indolinone-Based Glutarimides as Highly Efficacious and Selective IKZF2 Molecular Glue Degraders
Xuqing Zhang, Harshil Dhruv, Qiaolin Deng, Matthew Tudor, Nelisa Bechtel, Rakesh Nagilla, Larry J. Jolivette, Cory Rice, Peter P. Orth, Elham Behshad, Corey Strickland, Helai P. Mohammad, Longchuan Bai, Donna McEachern, Shaomeng Wang, Zhihua Sui, E. Scott Priestley
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% D max 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.