AP24534 demonstrated potent inhibition of selected additional kinase targets – the receptors for vascular endothelial growth factors (VEGFR), fibroblast growth factors (FGFR) and angiopoietin (Tie2) that control angiogenesis, and Flt3 kinase that plays a critical role in the pathogenesis of acute myeloid leukemia (AML). These findings support the broad potential of AP24534 not only in drug-resistant CML, but also in other hematological cancers, such as AML, and various solid tumors.
AP24534 potently inhibits all mutant forms of Bcr-Abl tested, including T315I, which is completely resistant to currently available drugs, and other partially resistant mutants, such as T315A. AP24534 was found to be more potent than dasatinib in animal models of early-stage CML (when the Bcr-Abl protein is not mutated). Even when given infrequently in these animal models, including single doses, AP24534 induced regression of tumors expressing unmutated or mutated forms of Bcr-Abl. AP24534 also potently inhibited the growth of primary human leukemia cells isolated from leukemia patients expressing these Bcr-Abl variants but it does not inhibit Aurora kinases, which differentiates it from other investigational T315I inhibitors.
Tim Clackson, chief scientific officer of Ariad, said: “These data illustrate the potential for AP24534 to treat several forms of leukemia and solid tumors based on its broad-acting and unique profile. We are on track to enroll patients with CML and other hematological malignancies in our first clinical trial of oral AP24534 in early 2008.”