Pyrrolo[3,2-d]pyrimidine derivatives capable of fitting into the ATP binding site of the HER2/EGFR protein were designed and synthesized. The clinical candidate, TAK-285, potently inhibited HER2 and EGFR with IC50 values of 17 and 23 nM, respectively, indicating selective inhibition of the HER family kinases. TAK-285 also inhibited the growth of the HER2-overexpressing human breast cancer cell line BT474 (GI50 17 nM). Furthermore, reflecting its good oral bioavailability, TAK-285 exhibited potent, dose-dependent efficacy in rats and inhibited the growth of HER2-overexpressing 4-1ST tumors with T/C of 38% and 14% at 6.25 and 12.5 mg/kg and, notably, tumor regression with T/C of -12% and -16% at 25 and 50 mg/kg.The first X-ray co-crystal structures of TAK-285 with HER2 and EGFR demonstrated TAK-285 interaction with the expected residues in their respective ATP pockets. Therefore, TAK-285 appears to be a promising candidate for clinical development as a novel HER2/EGFR dual kinase inhibitor.

Design and synthesis of novel HER2/EGFR dual inhibitors: Discovery of TAK-285 bearing a pyrrolo[3,2-<i>d</i>]pyrimidine scaffold

242nd National Meeting (2011)

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Design and synthesis of novel HER2/EGFR dual inhibitors: Discovery of TAK-285 bearing a pyrrolo[3,2-d]pyrimidine scaffold