9q2d
Cryo-EM structure of ternary complex Ikaros-ZF2:CC-885:CRBN:DDB1 (molecular glue degrader)
Structural highlights
DiseaseIKZF1_HUMAN Precursor B-cell acute lymphoblastic leukemia;Stevens-Johnson syndrome;Pancytopenia due to IKZF1 mutations. Defects in IKZF1 are frequent occurrences (28.6%) in acute lymphoblasic leukemia (ALL). Such alterations or deletions lead to poor prognosis for ALL. Chromosomal aberrations involving IKZF1 are a cause of B-cell non-Hodgkin lymphomas (B-cell NHL). Translocation t(3;7)(q27;p12), with BCL6. The disease is caused by mutations affecting the gene represented in this entry. FunctionIKZF1_HUMAN Transcription regulator of hematopoietic cell differentiation (PubMed:17934067). Binds gamma-satellite DNA (PubMed:17135265, PubMed:19141594). Plays a role in the development of lymphocytes, B- and T-cells. Binds and activates the enhancer (delta-A element) of the CD3-delta gene. Repressor of the TDT (fikzfterminal deoxynucleotidyltransferase) gene during thymocyte differentiation. Regulates transcription through association with both HDAC-dependent and HDAC-independent complexes. Targets the 2 chromatin-remodeling complexes, NuRD and BAF (SWI/SNF), in a single complex (PYR complex), to the beta-globin locus in adult erythrocytes. Increases normal apoptosis in adult erythroid cells. Confers early temporal competence to retinal progenitor cells (RPCs) (By similarity). Function is isoform-specific and is modulated by dominant-negative inactive isoforms (PubMed:17135265, PubMed:17934067).[UniProtKB:Q03267][1] [2] [3] [4] Publication Abstract from PubMedCullin-RING Ligase 4 Cereblon (CRL4(CRBN)) (CRBN) E3 ligase modulatory drugs (CELMoDs(TM)) make up a successful class of compounds targeting neosubstrates for proteasome-dependent degradation. Early immunomodulatory drugs (IMiDs(TM)) target Ikaros and Aiolos degradation. In addition, there are ongoing clinical trials targeting the degradation of biologically relevant proteins such as GSPT1, CK1alpha, and Helios with CRBN-based molecular glues. To date, most advanced preclinical and clinical CRBN-based molecular glues recruit their neosubstrates through canonical G-motifs, secondary protein features that are structurally similar but have significantly different amino acid sequence identities. Analogous to the development of kinase inhibitors, optimizing both neosubstrate recruitment and degradation selectivity is important to minimize potential off-target activity. Here, we describe a computational structure-based approach to analyze and predict putative ligand interactions important in the neosubstrate ternary complex. This approach provides valuable insights for enhanced designs toward the development of more selective and efficacious CRBN-based molecular glues. Application of Weighted Interaction-Fingerprints for Rationalizing Neosubstrate Potency and Selectivity of Cereblon-Based Molecular Glues.,Luchini G, Liu S, Powers HL, Cherney E, Zhu J, Danga K, Thompson JW, Shi L, Pagarigan B, Wei DD, Park P, Degnan AP, Zapf CW, Riggs JR, Johnson S, Cummins T J Med Chem. 2025 Sep 25. doi: 10.1021/acs.jmedchem.5c01919. PMID:40994183[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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