506
V. R. Doppalapudi et al. / Bioorg. Med. Chem. Lett. 17 (2007) 501–506
Table 1. ETA and ETB binding assaya results
xenograft model. Endothelin antagonists inhibit the
PC-3 and OVCAR-5 tumor xenograft growth, but
there have been no reports on the anti-tumor effects
of the biphenyl sulfonamides. In a prostate cancer
xenograft (PC-3) study, a 10 mg/kg once weekly dose
of CovX-Body 12 inhibited the tumor volume growth
by >45% by day 31, compared to the vehicle control.
In comparison, a 2 mg/kg daily dose of compound 1
showed 50% tumor growth inhibition by day 31
(Fig. 3). The individual components of a 20 mg/kg
dose of CovX-Body 12, antibody m38C2 alone
(20 mg/kg/once a week), and compound 2 alone
(0.25 mg/kg/once a week) failed to inhibit the tumor
growth. Thus, CovX-Body 12 is highly active at a
low concentration while compound 2 alone was inef-
fective even at dosages ꢁ40-fold higher, on a molar
basis, than those used for CovX-Body 12.
b
ETA IC50 (nM) ETB IC50 (nM) ETB/ETA
Compound
1
1.0
1.6
6003
1110
8978
1121
507
2
CovX-Body 12
8.6
4360
3
19
44.9
8.0
>10,000
4690
9370
564
1372
564
1372
420
95
CovX-Body 20
22
CovX-Body 23 14
7.2
7.7
4510
10,000
1910
570
27
4.6
6.0
CovX-Body 29
28
CovX-Body 30 15.6
21.6
4920
5170
228
331
a The inhibition of endothelin binding to ETA and ETB receptors stably
expressed on CHO cells was measured using 125I-labeled ET-1
competitive assays.
b IC50 values were calculated using means of at least three measure-
ments for six concentrations from 1 lM to 10 pM.
In conclusion, these studies establish the potential of
chemically programmed monoclonal antibodies like
CovX-Body 12 as a novel and effective class of immuno-
therapeutics that combine the merits of traditional small
molecule drug design with immunotherapy.
References and notes
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or ETB receptors13,14 (Table 1). In all binding assays, the
ETA targeting CovX-Bodies, the b-diketone analog, and
the parent small molecule compound 1 were evaluated.
Compound 2 showed an affinity for ETA similar to that
of the parent compound 1 (IC50 1.6 nM vs 1.0 nM). This
result is remarkable considering the presence of a long
PEG tether in compound 2 compared to compound 1.
The corresponding CovX-Body 12, with an IC50 of 8.6
nM, showed a marginal loss in the ETA binding affinity.
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with a corresponding alteration to the overall selectivity.
In contrast, compound 3 had an ETA binding affinity al-
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mor efficacy of CovX-Body 12 in a nude mouse/human