9OHR

Structure of CRBN:IKZF2:Compound 35

This is a non-PDB format compatible entry.

Summary for 9OHR

• Entry DOI: 10.2210/pdb9ohr/pdb
• Descriptor: Protein cereblon, Zinc finger protein Helios, (3S)-3-[(5M)-5-{1-(oxetan-3-yl)-4-[(pyrrolidin-1-yl)methyl]-1H-pyrrolo[2,3-b]pyridin-6-yl}-1-oxo-1,3-dihydro-2H-isoindol-2-yl]piperidine-2,6-dione, ... (5 entities in total)
• Functional Keywords: protein degrader, immune system
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 8
• Total formula weight: 65026.20

Authors

Strickland, C.O.,Rice, C.T. (deposition date: 2025-05-05, release date: 2025-09-03, Last modification date: 2025-09-24)

Primary citation

Zhang, X.,Dhruv, H.,Deng, Q.,Tudor, M.,Bechtel, N.,Nagilla, R.,Jolivette, L.,Rice, C.T.,Orth, P.,Behshad, E.,Strickland, C.,Mohammad, H.P.,Bai, L.,McEachern, D.,Wang, S.,Sui, Z.,Priestley, E.S.
Discovery of a Novel Series of iso -Indolinone-Based Glutarimides as Highly Efficacious and Selective IKZF2 Molecular Glue Degraders.
J.Med.Chem., 68:18230-18257, 2025

PubMed 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 -indolinone-based glutarimides, identifying compound as a potent, selective IKZF2 degrader with >90% 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, provides a foundation for further preclinical evaluation in cancer immunotherapy.

PubMed: 40842140
DOI: 10.1021/acs.jmedchem.5c00668

Experimental method

X-RAY DIFFRACTION (2.34 Å)