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Chemical Complementation of Androgen Receptor Mutations Associated with Androgen Independent Prostate Cancer
Author(s) -
Bourreza Aly Delores,
Koh John T.
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.5.a255-a
Subject(s) - bicalutamide , androgen receptor , flutamide , prostate cancer , androgen , lncap , antiandrogen , endocrinology , medicine , dihydrotestosterone , cancer research , enzalutamide , chemistry , cancer , hormone
Prostate cancer remains the second leading cause of cancer death in men. As prostate tissue is dependent on androgens for growth and homeostasis, anti‐androgens, such as flutamide and bicalutamide (Casodex®), used alone or in conjunction with chemical castration have been used in the treatment of prostate cancer for decades. However, as many as 30%–40% of patients treated with anti‐androgens become resistant to anti‐androgens within five years of treatment. The prevalence of androgen receptor (AR) mutations that caused flutamide resistance led to the adoption of bicalutamide as the drug of choice for prostate cancer treatment six years ago, however new bicalutamide resistant mutants, W741C and W741L, have recently been identified in the clinic. Bicalutamide acts as an agonist with these mutants. It is believed that anti‐androgens can be synthesized in such a way that they remain functional antagonists in mutant forms of the androgen receptor. The novel compounds were synthesized based on the crystal structure of anti‐androgen resistant AR mutants. The androgenic and anti‐androgenic effects of novel compounds in competition with synthetic androgen R1881 is evaluated using ARE‐luciferase reporter gene assays. In addition, anti‐androgen resistance can be simulated in vitro by culturing LNCaP cells in the presence of anti‐androgens for extended periods of time. Based on structural models we predict that these second generation AR antagonists will be resistant to AR mutations associated with anti‐androgen withdrawal syndrome.