targetsTarget

Cereblon (CRBN)

The protein that lenalidomide and pomalidomide latch onto. Bound drug changes which proteins the cell tags for destruction, degrading the myeloma transcription factors Ikaros and Aiolos.

Cereblon is the substrate receptor of the CRL4 E3 ubiquitin ligase. Thalidomide, lenalidomide and pomalidomide act as molecular glues: bound to cereblon they recruit new substrates, above all the lymphoid transcription factors IKZF1 (Ikaros) and IKZF3 (Aiolos), for ubiquitination and destruction, which kills myeloma cells and stimulates T and natural killer cells. In del(5q) myelodysplastic syndrome lenalidomide degrades casein kinase 1 alpha instead. This mechanism founded the field of targeted protein degradation and is the template for molecular glue degraders.

Cereblon (CRBN): what it is and how drugs act on it · animated generic schematic, not to scale

Target · the protein and the cell it sits on
Drug · antibody, small molecule, cell or radioligand
Effect · signal, damage or kill

In plain words · The protein that lenalidomide and pomalidomide latch onto. Bound drug changes which proteins the cell tags for destruction, degrading the myeloma transcription factors Ikaros and Aiolos.

1 · What it is
The protein that lenalidomide and pomalidomide latch onto. Bound drug changes which proteins the cell tags for destruction, degrading the myeloma transcription factors Ikaros and Aiolos.
2 · What goes wrong in cancer
Substrate receptor of the CRL4 (CUL4, DDB1, RBX1) E3 ubiquitin ligase; immunomodulatory drugs redirect it to degrade IKZF1, IKZF3 and CK1 alpha.
3 · How drugs use it
No product in this corpus aims at Cereblon (CRBN) yet. Drugs bind the molecule precisely: to switch it off, flag the cell for the immune system, or deliver a payload.