and IGF-R promotes tumor growth in vivo. 5 – 7 The IGF-R signaling pathway is also associated with acquired resistance toward a number of different antitumor agents hygiene including cytotoxic chemotherapeutics and radiation as well as other molecularly targeted agents. A growing body of data indicates that the insulin receptor (IR) also mediates tumor-cell growth and survival. 8 – 30 Given the important role of IGF-R and IR in cancer, these receptors have been intensely targeted for the design of anticancer therapeutics, and both biologic and small-molecule tyrosine kinase inhibitors of IGF-R and/or IR are currently in advanced clinical develop- ment.

Humanized mAbs that specifically neutralize IGF-R activity are being explored in the clinic; however, small molecules that dually inhibit IGF- R and IR may exhibit greater antitumor activity for tumors where both receptors are coexpressed and activated. OSI-906 is a small-molecule dual IGF-R/IR inhibitor currently in advanced clinical study. 3 OSI- 906 purchase mercaptopurine exhibits potent inhibition of both IGF-R and IR, but does not exhibit activity when evaluated against an extensive panel of other kinases. The discovery of this class of inhibitors began at OSI with various hit-to-lead identification techniques. These efforts ultimately led to the identification of a lead series of adenosine triphosphate (ATP) com- petitive IGF-R/IR inhibitors containing a unique imidazopyrazine template substituted with a ben- zyoxyphenyl moiety. 3 – 33 These compounds were selective for IGF-R and IR, but were unoptimized in respect to target potency as well as for drug metabolism and buy mercaptopurine pharmacokinetic (DMPK) properties.

In order to facilitate structure-based design efforts to complement ongoing lead-optimization medici- nal chemistry efforts, OSI initiated a collaboration with Dr Todd Miller (Stony Brook University) and Dr Steven Hubbard (New York University) to deter- mine the cocrystal structure for a lead compound of the benzyloxyphenyl-derived imidazopyrazine series with the catalytic domain of IR. Dr Hubbard had previously determined the crystal structures for these receptors and is an expert in understanding pro- tein tyrosine kinase function at the structural level. 5 M OUNT S INAI J OURNAL OF M EDICINE 363 Fig . Co-crystal structure of lead OSI compounds bound to IR. Dr Miller is an expert in the molecular mechanism for receptor tyrosine kinase signaling. Working together with OSI scientists, Dr Hubbard’s and Dr Miller’s groups determined the cocrystal structure of a lead OSI compound and IR (Figure ). Additionally, this cocrystal structure allowed for the construction of an IGF-R homology model. Both cocrystal structure and Lapatinib homology modeling –based efforts, in conjunc- tion with computer-assisted drug design (CADD) and medicinal chemistry efforts at OSI, led to the real- ization of key determinants of binding (Figure ) for compounds within this series to both receptors that contributed to further maturation of the com- pound series.

For example, critical hydrogen bond- ing interactions between compound and residues within the IR and IGF-R catalytic domains were made evident, allowing insight into motifs that had to be preserved to maintain efficient binding. In addition to elucidating key binding determinants, important structural observations were made: () the existence of an Pimobendan unoccupied hydrophobic pocket adja- cent to the molecule, and () the coplanar nature and bioactive conformation of the benzyloxyphenyl pharmacophore. Based on these observations, a ratio- nal structure-based drug-design approach ensued hydrophobic pocket F07 A0 E050 at OSI, leading to the replacement of the benzy- loxyphenyl moiety with -phenyl-quinolin-7-yl. The resulting molecule exhibited a 0-fold improvement in receptor binding as well as improved DMPK properties. A subsequent IGF-R crystal structure in col- laboration with Drs. Miller and Hubbard was deter- mined for an advanced quinolinyl lead molecule PQIP.