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 73

dependence on other growth factors. 13 Ablation of IGF-1R signaling through
targeted down-regulation of receptor expression using siRNA or inhibiting
receptor activity using small-molecule tyrosine kinase inhibitors (TKIs),
receptor neutralizing antibodies, or dominant negative constructs has been
shown to inhibit tumor cell growth and survival both in vitro and in vivo. 14-19
The ability of tumor cells to exploit IGF-1R signaling is further underscored by
the observed loss of imprinting (LOI) for the gene encoding IGF-2 ligand,
leading to an increase in IGF-2 protein levels. 20-25 Such tumor cells that harbor
an autocrine IGF loop have been found to be especially sensitive to agents
targeting IGF-1R/IR.
In addition to its role in metabolic signaling, there is growing support for the
involvement of IR in tumor mitogenic signaling. The IR can be transforming
for both fibroblasts and mammary epithelial cells, and insulin can activate
tumoral AKT signaling in both the in vivo and in vitro settings. 26,27 Epide-
miological studies provide further support for the role of insulin signaling in
tumor growth. For a number of tumor types, including breast and prostate,
increased levels of insulin and C-peptide are associated with poor prog-
nosis. 2,28,29 Furthermore, it has recently been reported that inhaled insulin is
associated with increased risk of lung cancer. 30 These observations support the
potential for enhanced and broader anti-tumor activity for IGF-1R/IR TKIs
compared to selective IGF-1R inhibition using anti-IGF-1R antibodies.
4.2 IGF-1R/IR Inhibitors as Anchors for
Combinatorial Anti-cancer Drug Strategies
IGF-1R/IR signaling can mediate activation of cellular survival in the presence
of a multitude of other anti-tumor agents, including cytotoxic chemother-
apeutics and radiation as well as molecular targeted therapies (MTTs). 31 The
ability for IGF-1R/IR inhibitors to augment the ecacy for these agents has
been extensively investigated in the preclinical setting and is the rational
underpinning for a multitude of combinatorial drug strategies being explored in
the clinical setting.
Herein, we describe the path leading to the discovery and development of
OSI-906, a selective, orally bioavailable, low molecular weight, dual inhibitor
of IGF-1R and IR. This discovery was enabled through the use of rational,
structure-based drug design to optimize both the binding anity for IGF-1R/
IR and achieve a high degree of selectivity versus other kinases. Empirical
medicinal chemistry in combination with high-speed analoging synthetic stra-
tegies were utilized to expedite the optimization process. Finally, a streamlined
testing cascade of in vitro and in vivo IGF-1R and IR models were used to assess
for pharmacokinetics (PK), pharmacodynamics (PD), ecacy, and safety, as
well as to enable structure-activity development, compound stratification, and
optimization. Finally, biomarker and combinatorial drug strategies were
applied to facilitate a clinical development plan for this agent.