Definition

An orally bioavailable small molecule modulator of cereblon (CRBN), part of the cullin 4-RING E3 ubiquitin ligase complex (CRL4-CRBN E3 ubiquitin ligase; CUL4-CRBN E3 ubiquitin ligase), with potential immunomodulating and antineoplastic activities. Upon oral administration, CRBN modulator BTX-1188 specifically targets and binds to CRBN, thereby affecting the ubiquitin E3 ligase activity. This leads to ubiquitination and induces proteasome-mediated degradation of the hematopoietic transcription factors Ikaros (IKZF1) and Aiolos (IKZF3), which are transcriptional repressors in T cells, and the degradation of the protein neosubstrate G1 to S phase transition 1 (GSPT1), a translation termination factor. This reduces the levels of these transcription factors, and modulates the activity of the immune system, which, may include the activation of T lymphocytes. In addition, the degradation of the proteins IKZF1/3 and GSPT1 may lead to the downregulation of other proteins that play key roles in the proliferation of certain cancer cell types. CRBN, the substrate recognition component of the E3 ubiquitin ligase complex, plays an important role in the ubiquitination of certain proteins.