Discovery of a Novel Series of <i>iso</i>-Indolinone-Based Glutarimides as Highly Efficacious and Selective IKZF2 Molecular Glue Degraders
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 <i>iso</i>-indolinone-based glutarimides, identifying compound <b>55</b> as a potent, selective IKZF2 degrader with >90% <i>D</i><sub>max</sub> 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, <b>55</b> provides a foundation for further preclinical evaluation in cancer immunotherapy.
Authors
- Larry J. Jolivette
- Nelisa Bechtel
- Elham Behshad
- Harshil Dhruv (ORCID: https://orcid.org/0000-0003-2571-6649)
- Rakesh Nagilla
- Cory Rice (ORCID: https://orcid.org/0000-0003-2270-030X)
- E. Scott Priestley (ORCID: https://orcid.org/0000-0001-8390-1143)
- Longchuan Bai (ORCID: https://orcid.org/0000-0003-1025-2925)
- Qiaolin Deng (ORCID: https://orcid.org/0000-0001-6378-3872)
- Xuqing Zhang
- Donna McEachern (ORCID: https://orcid.org/0000-0001-8662-3425)
- Shaomeng Wang (ORCID: https://orcid.org/0000-0002-8782-6950)
- Peter P. Orth (ORCID: https://orcid.org/0000-0003-2183-8120)
- Matthew Tudor (ORCID: https://orcid.org/0000-0001-8766-195X)
- Corey Strickland
- Zhihua Sui
- Helai P. Mohammad
Institutions
- University of Michigan (US)
- DE Technologies (United States) (US)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-08-22
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c00668
- Citations
- 2
- Primary Topic
- Protein Degradation and Inhibitors
- Type
- article
- Field-Weighted Citation Impact
- 1.61