Cereblon (CRBN)-mediated protein degradation and Cytochrome P450 17A1 (CYP17A1) inhibition axis (CRBN/CYP17A1 axis)

The CRBN-mediated degradation axis in combination with CYP17A1 inhibition is a therapeutic strategy designed to treat advanced prostate cancer by targeting the androgen signaling pathway at two distinct levels. Cereblon (CRBN) is an E3 ubiquitin ligase substrate receptor that, when engaged by Proteolysis Targeting Chimeras (PROTACs), facilitates the ubiquitination and subsequent degradation of the androgen receptor (AR) [Source: UniProt Q96SW2]. Cytochrome P450 17A1 (CYP17A1) is a dual-function enzyme essential for the biosynthesis of androgens in both gonadal and extragonadal tissues [Source: UniProt P05093]. Abiraterone acetate is a small-molecule inhibitor of CYP17A1 that effectively shuts down the production of testosterone and dihydrotestosterone [Source: PubChem CID 132971]. By combining these two approaches, the strategy aims to deplete the AR protein itself while simultaneously removing the hormonal triggers that drive its activity. This combination is particularly relevant for patients with metastatic castration-resistant prostate cancer (mCRPC) who have developed resistance to standard androgen deprivation therapies through AR mutations or overexpression [Source: PubMed: 35641431]. This dual-targeting approach represents a significant advancement in overcoming the limitations of traditional AR antagonists by providing a more comprehensive blockade of the androgen signaling axis [Source: ClinicalTrials.gov NCT03888612].

Other names

CRBN-CYP17A1 dual inhibitionAR PROTAC and Abiraterone combinationCereblon-CYP17A1 therapeutic axisAndrogen receptor degradation and steroidogenesis inhibition

Dual-action strategy involving the recruitment of the Cereblon (CRBN) E3 ligase to induce proteasomal degradation of the androgen receptor while simultaneously inhibiting the Cytochrome P450 17A1 (CYP17A1) enzyme to block extragonadal androgen synthesis.