The Aurora family of serine/threonine kinases (Aurora-A, -B, -C) regulate cell-cycle progression in mammalian cells. Whereas Aurora-C function appears restricted to meiosis in males, Aurora-A and -B are essential for proper chromosome congression, segregation, and cytokinesis during mitosis. These mitotic kinases have been implicated in tumorigenesis, with overexpression levels correlating to clinical staging of cancers and poor prognosis, and thus have been the subject of much interest as targets for anticancer therapy. N-(4-((3-(2-amino-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-4-phenyl-1-phthalazinamine was a key Aurora kinase inhibitor lead, possessing oral bioavailability in rats that was lacking in the anthranilamide compounds from which it was derived. This phthalazine compound possessed a key feature that was deemed important to maintain in a clinical candidate: potency against a model multidrug resistant (MDR) cell line (MES-SA Dx5) commensurate with its activity against cell lines that do not overexpress P-gp. Improved in vivo potency was desired, as measured by suppression of the phosphorylation of the Aurora-B substrate Histone H3 (Ser10) in vivo. SAR from targeting this improvement uncovered a delicate balance between pharmacokinetic parameters and cell potency in MES-SA Dx5 cells. AMG 900 was identified as a suitable candidate for clinical development based on its low single digit nanomolar potency against MDR cell lines, robust pharmacodynamic response, and high selectivity against other kinases. Oral administration of AMG 900 at well-tolerated doses using three distinct schedules significantly inhibited the growth of HCT116 tumor xenograft cells in vivo. AMG 900 is currently undergoing phase 1 clinical evaluation in patients with advanced cancers.

Discovery of AMG 900, a highly selective, orally bioavailable inhibitor of Aurora kinases with efficacy in preclinical antitumor models and activity against multidrug-resistant cancer cell lines

248th National Meeting (2014)

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