IKZF1 (Ikaros)
Ikaros is a transcription factor that myeloma cells depend on. Lenalidomide, pomalidomide and the newer CELMoDs work by gluing Ikaros to the cell's disposal machinery so it is destroyed, which kills the plasma cell and wakes up T cells.
Overview
IKZF1 (chromosome 7p12.2) encodes Ikaros, a zinc-finger transcription regulator of haematopoietic differentiation and B- and T-lymphocyte development that binds gamma-satellite DNA, activates the CD3-delta enhancer, represses TDT during thymocyte differentiation, and regulates transcription through HDAC-dependent and independent complexes and the NuRD and BAF chromatin remodellers; dominant-negative isoforms modulate its function (UniProt Q13422). In OnCo it is the neosubstrate that thalidomide, lenalidomide and pomalidomide recruit to cereblon for ubiquitination and proteasomal degradation, and that golcadomide, a cereblon E3 ligase modulator, degrades alongside Aiolos; the loss lowers IRF4 and MYC in myeloma cells and stimulates T cells.
- Target · the protein and the cell it sits on
- Drug · antibody, small molecule, cell or radioligand
- Effect · signal, damage or kill
In plain words · Ikaros is a transcription factor that myeloma cells depend on. Lenalidomide, pomalidomide and the newer CELMoDs work by gluing Ikaros to the cell's disposal machinery so it is destroyed, which kills the plasma cell and wakes up T cells.
- 1 · What it is
Ikaros is a transcription factor that myeloma cells depend on. Lenalidomide, pomalidomide and the newer CELMoDs work by gluing Ikaros to the cell's disposal machinery so it is destroyed, which kills the plasma cell and wakes up T cells.
- 2 · What goes wrong in cancer
Ikaros is degraded rather than inhibited: the immunomodulatory drugs bind cereblon in the CRL4 ubiquitin ligase and change its substrate preference so that Ikaros and Aiolos are ubiquitinated and destroyed (lenalidomide mechanism steps).
- 3 · How drugs use it
4 products aim at IKZF1 (Ikaros): degraders. Transcription factors have no pocket to plug, so drugs either degrade them or block the partner protein they need to dock on DNA.
External identifiers
Biology
Ikaros is degraded rather than inhibited: the immunomodulatory drugs bind cereblon in the CRL4 ubiquitin ligase and change its substrate preference so that Ikaros and Aiolos are ubiquitinated and destroyed (lenalidomide mechanism steps). The lenalidomide record calls this the basis for CELMoDs and molecular-glue degraders generally.
- Multiple myeloma (degradation by immunomodulatory drugs and CELMoDs)
- Diffuse large B-cell lymphoma (lenalidomide; golcadomide trials)
- Kaposi sarcoma (pomalidomide)
Golcadomide is a next-generation lenalidomide-like pill that degrades two lymphoma transcription factors far more potently, now in phase 3 with R-CHOP.
Lenalidomide is a thalidomide descendant that glues the proteins IKZF1 and IKZF3 to cereblon so the cell destroys them, killing plasma cells and rousing T cells. It is the backbone of myeloma treatment and maintenance, also used in mantle cell and follicular lymphoma, and generic since 2022.
The third-generation thalidomide analogue for myeloma that has failed lenalidomide, and since 2020 the first new drug for Kaposi sarcoma in two decades.
Thalidomide is the drug behind the 1960s birth-defect tragedy, rehabilitated as the first immunomodulatory myeloma drug and the parent of lenalidomide and pomalidomide.
Notes
top- Prevalence not recorded in this wave: HGNC and UniProt carry no positivity rates and no other source was consulted.
Latest papers
topQuery for this target: (TITLE:"IKZF1" OR ABSTRACT:"IKZF1" OR TITLE:"Ikaros" OR ABSTRACT:"Ikaros" OR TITLE:"IKAROS" OR ABSTRACT:"IKAROS" OR TITLE:"ZNFN1A1" OR ABSTRACT:"ZNFN1A1" OR TITLE:"IKAROS family zinc finger 1" OR ABSTRACT:"IKAROS family zinc finger 1") AND (cancer OR tumor OR tumour OR oncology OR carcinoma OR lymphoma OR leukemia OR leukaemia OR myeloma OR sarcoma OR melanoma OR glioma). Results are unfiltered search hits about IKZF1 (Ikaros), not a curated reading list.
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