Novel Androgen Receptor Antagonists for the Treatment of Prostate Cancer - Accounts in Drug Discovery Case Studies in Medicinal Chemistry - page 121

initial favorable response, most tumors advance to a hormone-refractory
prostate cancer (HRPC) stage in an average of 18 months. The designation
hormone-refractory is misleading, since there is clear dependence on AR sig-
naling even in the most advanced forms of HRPC. Microarray-based profiling
of isogenic hormone-sensitive and hormone-refractory human prostate cancer
xenograft mouse pairs indicated that AR mRNA was upregulated in all HRPC
models. 4 Serum prostate specific antigen (PSA), the secreted protein product of
an AR-regulated gene, is the most prognostic biomarker for prostate cancer. 1
PSA declines after initiation of hormone depletion therapy, and a subsequent
rise is commonly the first sign of disease progression. This indicates that
reactivation of AR signaling accompanies the development of HRPC. Analyses
of tumor samples from patients with HRPC have suggested several mechanisms
used by tumor cells to reactivate AR signaling, including gene amplification
and increased expression of the AR protein, and selection of point mutations in
the AR LBD that can result in activation by non-androgenic ligands. Taken
together, these findings suggest that more potent AR pan-antagonists than
bicalutamide may provide additional clinical benefits in the treatment of
prostate cancer.
6.2 Bristol-Myers Squibb Approach
6.2.1 Strategy
The goal of the Bristol-Myers Squibb (BMS) AR antagonist program was to
identify a new generation of anti-androgens with improved binding and func-
tional AR antagonist potency over nonsteroidal clinical anti-androgens, such
as bicalutamide, nilutamide, and flutamide. 2 2-Hydroxyflutamide is the major
metabolite of flutamide, with higher binding anity for AR than the parent
compound. Clinical utility of flutamide and nilutamide has been restricted due
to the observed hepatotoxicity after prolonged administration. Bicalutamide is
the preferred clinical anti-androgen because of its long half-life and sig-
nificantly reduced liver toxicity. However, patients on bicalutamide are also
susceptible to the anti-androgen withdrawal syndrome (AWS), a clinical phe-
nomenon described in terms of decreasing PSA values and clinical improve-
ment. 5 AR gene mutation to a form that can accommodate the anti-androgen
in an agonist conformation has been offered as a plausible explanation for the
observed AWS. Indeed, bicalutamide has been shown to work as an agonist for
the W741C and W741L mutant variations of AR. 5b Therefore, the program
objective was to develop full antagonists against both wild-type as well as
known mutant AR isoforms. Since bicalutamide is frequently employed as part
of the initial treatment regimen for prostate cancer, it was important to
demonstrate ecacy for refractory prostate tumors previously treated with
bicalutamide. Existing experience suggested that complete and sustained AR
antagonism for the entire duration of treatment was essential in order to
observe a robust anti-tumor response. Indeed, mean steady-state concentration