Definition

An orally bioavailable avadomide derivative, which contains the stable, active (S)-enantiomer form of avadomide, and modulator of cereblon (CRBN), which is 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 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. 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 IKZF1 and IKZF3 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. SP3164 uses deuterium to stabilize the (S)-enantiomer of avadomide and prevent interconversion to the undesired (R)-enantiomer, which increases the binding affinity to CRBN.