2. Academic Validation
  3. Discovery of a Novel Series of iso-Indolinone-Based Glutarimides as Highly Efficacious and Selective IKZF2 Molecular Glue Degraders

Discovery of a Novel Series of iso-Indolinone-Based Glutarimides as Highly Efficacious and Selective IKZF2 Molecular Glue Degraders

  • J Med Chem. 2025 Sep 11;68(17):18230-18257. doi: 10.1021/acs.jmedchem.5c00668.
Xuqing Zhang 1,  Harshil Dhruv 1,  Qiaolin Deng 1,  Matthew Tudor 1,  Nelisa Bechtel 1,  Rakesh Nagilla 1,  Larry Jolivette 1,  Cory T Rice 1,  Peter Orth 1,  Elham Behshad 1,  Corey Strickland 1,  Helai P Mohammad 1,  Longchuan Bai 2,  Donna McEachern 2,  Shaomeng Wang 2,  Zhihua Sui 1,  E Scott Priestley 1
Affiliations

Affiliations

  • 1 SK Life Sciences Laboratories, 2500 Renaissance Boulevard, King of Prussia, Pennsylvania 19406, United States.
  • 2 The Rogel Cancer Center, Department of Internal Medicine, Department of Pharmacology, and Department of Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan 48109, United States.
PMID: 40842140 DOI: 10.1021/acs.jmedchem.5c00668
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.

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