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 93

Figure 4.10 OSI-906 docked in IGF-1R. View into the ATP-binding pocket: (A) from
the side opposite the hinge motif and (B) from above the N-terminal
lobe. The C{a} trace of IGF-1R is given in green, with the C-helix in red
and the termini of the activation loop in purple. OSI-906 features yellow
carbons. The C-helix is positioned in nearly identical orientation relative
to the remainder of the N-terminal lobe as in 0P structures of IGF-1R or
IR. The activation loop has a trajectory that goes out and away from the
ATP binding site before returning to the C-terminal lobe, a trajectory
distinct from those observed in 0P structures of IGF-1R and IR.

Table 4.14 Microsomal stability and CYP450 profiles of OSI-906.

Inhibition of human pIR in cells

Cell line IC 50 (mM)

Hepa-1 0.039

Microsomal stablilty of OSI-906

Species Mouse Rat Dog Human

Extraction ratio 0.54 0.41 0.49 0.55

Cytochrome P450 profile of OSI-906

CYP isoform IC 50

3A4 410

2D6 410

1A2 410

fashion. 48-51 With emerging data supporting a role for the insulin receptor,
alone and in combination with IGF-1R in cancer, we further profiled OSI-906
for activity against the insulin receptor in the cellular setting. The effects of
OSI-906 against human pIR inhibition in cells was measured in a murine-
derived hepatoma cell line (Hepa-1) and afforded an IC 50 value of 39 nM
(Table 4.14). This result, in conjunction with a high degree of selectivity against
a wide panel of kinases, establishes OSI-906 as a highly selective dual inhibitor
of both IGF-1R and IR. In addition to its high degree of selectivity versus a