TOK-001 (Galeterone) is a novel small molecule that selectively target CYP17 and androgen receptor for prostate cancer treatment [1].
CYP17 and androgen receptor (AR) are two preferred target during the treatment of prostate cancer: The former is the prime enzyme that responsible for the production of cancer-inducing androgens [1], whereas the latter acts as transcription factor that increases the expression of androgen-responsive genes [2].
Galeterone is a small molecular therapeutics that designed to treat prostate cancer in three distinctive pathways: competitively inhibit the enzyme function of CYP17. Decreasing androgen-responsive genes expression by binding to AR, and downregulates AR population [3]. Using 293T cells transfected with CYP17, galeterone inhibited the lyase function of CYP17 with an IC50 value of 47 nM after 18 hrs of incubation [3]. In prostate cancer cell line assay, galeterone inhibited the proliferation of LNCaP and LAPC-4 with IC50 value of 6 and 3 μM, respectively [3].
In mice xenograft model that inoculated with LAPC4 cell lines, a daily subcutaneous injection of galeterone (0.15 mmol/kg, twice per day) reduced both the average volume and weight of tumour less by more than 80% and 50%, respectively in comparison with control group [3]. Galeterone is currently underwent phase III clinical trails for castration-resistant prostate cancer.
References:
[1].?Devore N M, & Scott E E. Structures of cytochrome P450 17A1 with prostate cancer drugs abiraterone and TOK-001. Nature, 2012, 482: 116-119.
[2].?Mallik I, Davila M, Tapia T, et al. Androgen regulates Cdc6 transcription through interactions between androgen receptor and E2F transcription factor in prostate cancer cells. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, 2008,1783:1737-1744.
[3].?Bruno R D, Vasaitis T S, Gediya L. K, et al. Synthesis and biological evaluations of putative metabolically stable analogs of VN/124-1 (TOK-001): Head to head anti-tumor efficacy evaluation of VN/124-1 (TOK-001) and abiraterone in LAPC-4 human prostate cancer xenograft model. Steroids, 2011,76: 1268-1279.
