A metabolite of abiraterone is more effective than the parent drug

Zytiga (abiraterone) is a blockbuster drug for the treatment of metastatic castration-resistant prostate cancer. The total sales for 2014 reached $2.24 billion. Innocrin Pharmaceuticals and Tokai Pharmaceuticals (NASDAQ: TKAI) are developing me-better versions of abiraterone (VT-464 and galeterone).

Cleveland Clinic researchers found that D4A, a major metabolite of abiraterone, is more effective than the parent drug[1]. D4A inhibits not only CYP17A1, but also 3βHSD and SRD5A, which are required for DHT synthesis. Furthermore, D4A is a competitive, potent androgen receptor antagonist (IC50=7.9 nM).


The researchers examined the effects of D4A in two prostate cancer xenograft models. D4A is more potent than abiraterone for blocking VCaP and C4-2 xenograft progression. Direct treatment with D4A is likely to result in a greater clinical benefit than abiraterone.

[1] Nature. 2015, doi: 10.1038/nature14406.

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