Novel Androgen Receptor Antagonists for the Treatment of Prostate Cancer - Accounts in Drug Discovery Case Studies in Medicinal Chemistry - page 135

Further optimization of SAR and PK properties led to the identification of
BMS-779333, a potent AR antagonist with potential to meet the criteria set for
the AR backup program. As shown in Table 6.2, BMS-779333 exhibited AR
binding potency and functional antagonism that are superior to bicalutamide
and comparable to the clinical candidate, BMS-641988. 19 The activity of BMS-
779333 on different mutant AR forms was compared against bicalutamide,
BMS-641988, and BMS-949 in PC3 cells (AR negative) co-transfected with
either the wt or variant AR expression constructs and an AR-dependent (PSA
promoter driven) luciferase reporter construct (Figure 6.10). As expected, the
natural ligand DHT stimulated luciferase expression of all the AR (wt and
mutant) forms tested. BMS-779333 did not show significant agonist activity for
the wt AR, the mutant AR expressed in the LNCaP cells (T877A), or the CWR-
22-BMSLD1 human prostate cancer cells (H874Y), or the two mutants pre-
viously described to be activated by bicalutamide (W741C and W741L). [1c] In
contrast to BMS-641988, no agonistic activity for Flag-AR-LNCaP cell pro-
liferation was observed for BMS-779333. Docking studies suggested that
regardless of the size of the amino acid residue at the 877 position (i.e., T877 vs.
A877), the hydroxyl group of BMS-779333 may clash with the backbone of
amino acid 877 in the LBD of AR (Figure 6.11). Thus, BMS-779333 is unlikely
to be accommodated in the agonist conformation and may promote partial
unfolding of AR. This offers a plausible explanation for the observed pan-
antagonist profile of BMS-779333.
In the CWR-22-BMSLD1 tumors, BMS-779333 exhibited ecacy superior
to bicalutamide and comparable to that of BMS-641988. Tumors that failed
bicalutamide treatment were shown to retain their sensitivity to respond to
BMS-779333. In the LuCaP 23.1 tumor xenografts, BMS-779333 produced
significant delay in tumor growth and time to progression to target size
along with a major reduction of PSA levels compared to the control group.
In this model, the minimum ecacious dose was determined to be 4.2mg kg 1

DMSO DHT Bicalutamide BMS-949 BMS-641988 BMS-779333

160

140

120

100

80

60

40

20

0

GFP AR WT AR T877A

(LNCaP)

AR H874Y
(CWR22)

AR W741C AR W741L

Transfection

Figure 6.10 Comparison of BMS-779333, BMS-641988, BMS-949, bicalutamide, and
DHT in transactivation assays in PC3 cells expressing exogenous wt or
various mutant forms of AR (all compounds at 1 mM concentration).