The Discovery of OSI-906, a Small-molecule Inhibitor of the Insulin-like Growth Factor-1 and Insulin Receptors - Accounts in Drug Discovery Case Studies in Medicinal Chemistry - page 94

Table 4.15 Antiproliferative effects of OSI-906 versus sensitive tumor cell lines. a

EC 50
(mM) b

EC 50
(mM) b Tumor type Cell line Tumor type Cell line

LISN NIH-3T3 0.078 NSCLC H358 0.117
Colorectal HT29 0.072 H292 0.235
Colo205 0.098 H322 0.319
GEO 0.021 Calu1 0.830
SW620 0.021 H441 0.152
SW480 0.191 DU4475 0.086
Pancreatic BxPC3 0.150 Breast MCF7 0.177
Rhabdomyosarcoma A673 0.153 SKBR3 0.635
a Proliferation monitored using the CellTiterGlo t luciferase-based cellular ATP assay kit (Pro-
mega). Conditions: 0.5% FCS þ IGF-1.
b EC 50 values ranged 0.025 mM.

wide array of kinases, OSI-906 was screened for microsomal stability against
mouse, rat, dog, monkey, and human liver microsomes, as well as for P450 drug-
drug interactions (Table 4.14). Overall, the microsomal stability of OSI-906 is
consistent and favorable across all species tested. The CYP450 profile for OSI-
906 is also favorable, with no anticipated CYP related drug-drug interactions.

4.10 OSI-906: Antiproliferative Effects
In cell-based phenotypic assays, OSI-906 inhibited IGF-1- or IGF-2-mediated
proliferation (and induced apoptosis, data not shown) in cell lines representing
a range of tumor types. 39 A variety of tumor cell lines exhibit differential
sensitivity to OSI-906, with EC 50 values ranging from 0.021 to 0.830 mM
(Table 4.15). These data suggest that the activated IGF-1R within these cells is
required to maintain proliferation and survival and can be inhibited by treat-
ment with OSI-906. To further validate that both IR and IGF-1R are co-
inhibited in tumor cells sensitive to OSI-906, the effects of OSI-906 on the
phosphorylation of IR and IGF-1R was determined by RTK capture array.
For both HT-29 and Colo205 CRC cells, OSI-906, at a concentration of 1 mM,
fully inhibits both IR and IGF-1R phosphorylation (Figure 4.11).

4.11 OSI-906: Pharmacokinetic Properties
The pharmacokinetic parameters obtained from non-compartmental modeling
following iv administration of OSI-906 in the female CD-1 mouse, female
Sprague Dawley rat, and the male beagle dog are summarized in Table 4.16. 39
In the mouse and the rat, the clearance is relatively low, with elimination half-
lives of 2-3 h, and in the dog the clearance is 39mLmin 1 kg 1 , which is
approximately equal to the liver blood flow, with a shorter half-life around 1 h.
The volume of distribution at steady state (V ss ) is less than 5 L kg 1 in each

species, significantly lower than that observed with PQIP and AQIP,