9ohq
From Proteopedia
Structure of CRBN:IKZF2:Compound 15
Structural highlights
DiseaseCRBN_HUMAN Autosomal recessive nonsyndromic intellectual deficit;Distal monosomy 3p. The disease is caused by mutations affecting the gene represented in this entry. FunctionCRBN_HUMAN Component of some DCX (DDB1-CUL4-X-box) E3 protein ligase complex, a complex that mediates the ubiquitination and subsequent proteasomal degradation of target proteins and is required for limb outgrowth and expression of the fibroblast growth factor FGF8. In the complex, may act as a substrate receptor. Regulates the assembly and neuronal surface expression of large-conductance calcium-activated potassium channels in brain regions involved in memory and learning via its interaction with KCNT1.[1] [2] Publication Abstract from PubMedImmunosuppressive 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. Discovery of a Novel Series of iso-Indolinone-Based Glutarimides as Highly Efficacious and Selective IKZF2 Molecular Glue Degraders.,Zhang X, Dhruv H, Deng Q, Tudor M, Bechtel N, Nagilla R, Jolivette L, Rice CT, Orth P, Behshad E, Strickland C, Mohammad HP, Bai L, McEachern D, Wang S, Sui Z, Priestley ES J Med Chem. 2025 Aug 21. doi: 10.1021/acs.jmedchem.5c00668. PMID:40842140[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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