ture confirmed the predicted bind- ing mode and validated the IGF-R homology model. Further medicinal chemistry refinement of the series at OSI ultimately led to a best-in-series dual IGF-R/IR inhibitor, OSI-906 (Figure 3). Paralleling in vitro autophosphorylation STI-571 assays in the Miller lab allowed realization that compounds such as PQIP and OSI-906 bind to both the unphosphorylated ‘‘inac- tive’’ receptor as well as the tris-phosphorylated ‘‘acti- vated’’ receptor. This binding characteristic is unique compared with other receptor tyrosine kinases that are currently clinically approved, including lapatinib (binding only to the inactive conformation) and erlotinib (binding only to the active conformation).

This distinguishing binding characteristic is linked to the atypical binding mode of this class of compounds, which upon binding to the ATP pocket induce the Fig 3. Schematic meropenem Merrem illustrating the progression of a lead IGF-R inhibitor series at OSI, culminating in the IND compound OSI-906, which is currently in advanced clinical development. expulsion of the activation loop from the active site and force the loop to adopt an extended confor- mation that is neither autoinhibitory nor active. This unique binding mode is proposed to explain the high degree of selectivity noted with this series of dual IGF-R/IR inhibitors. The iterative collaboration between OSI Pharmaceuticals and researchers at neighboring universities illustrates how industrial and academic resources can be leveraged in the discovery of antitumor therapeutics. The iterative collaboration between OSI Pharmaceuticals and researchers at neighboring universities illustrates how industrial and academic resources can be leveraged in the discovery of antitumor therapeutics.

CONCLUSION In the past, cancer target identification for therapeu- tic intervention and advanced clinical studies were the domain of academia. Drug discovery, develop- ment, and diagnostics were primarily the domain of industry. Recently, industry has taken a more active role in target identification and development, as exemplified by trastuzumab, and academia has demonstrated that it can be actively engaged in drug development, as exemplified by cetuximab. The dis- covery and development of OSI-906 and imatinib meropenem 96036-03-2 illustrates how industry and academia have worked together throughout many aspects and phases of drug discovery and development. Industry-academia collaborations continue to evolve in the new era of biomarker discovery and validation to support the development of truly personalized therapies. These DOI:0.00/MSJ examples serve as models that can be used to guide future drug discovery and washing hands development efforts, where collaborations between industry and academia accel- erate both scientific innovation and the delivery of improved therapies to patients suffering from devas- tating diseases like cancer. DISCLOSURES Potential conflict of interest: EB, MM, and KI are employees of OSI Pharmaceuticals. REFERENCES . Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol 00;

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