Preclinical anti-tumor efficacy of BMS-599626, a potent and highly selective inhibitor of HER1 (EGFR) and HER2 kinases

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Agents that selectively target each of the two receptor tyrosine kinases HER1 (EGFR) and HER2 have been approved for the treatment of solid tumors that overexpress these kinases. These selective agents (trastuzumab, cetuximab, and gefitinib) have been shown to inhibit primarily receptor homo-dimers. There remains considerable interest in identifying novel agents that may have improved efficacy, such as by inhibiting heterodimer as well as homodimer signaling. A series of novel pyrrolotriazine analogs have been optimized for the inhibition of both HER1 and HER2 and the proliferation of tumor cells that depend on HER1/HER2 signaling. Lead optimization led to the identification of BMS-599626, a compound that has shown desirable pharmacokinetic and ADME properties, in addition to favorable anti-tumor efficacy in preclinical models. In addition to inhibiting HER1 and HER2 kinase activity, BMS-599626 also inhibits the formation of HER1/HER2 heterodimer formation. The compound inhibits the proliferation of tumor cell lines that express moderate to high level of each or both of the two receptor kinases. Selectivity evaluation of BMS-599626 showed that the compound is highly selective for HER1 and HER2, with no significant inhibition or interaction with >100 diverse protein kinases tested. The selectivity of BMS-599626 is further supported by the fact that pharmacogenomic analyses revealed HER2 expression as the predominant predictor of sensitivity of breast tumor cell lines to inhibition by the compound. BMS-599626 has significant anti-tumor efficacy in multiple HER1- and HER2-dependent xenograft models, and tumor growth inhibition correlates with inhibition of receptor signaling in the treated tumors. BMS-599626 has excellent oral bioavailability in multiple species and efficacy in xenograft models was achieved with once daily oral dosing. On the basis of its preclinical profile, BMS-599626 was selected for evaluation in phase I clinical studies.