[0010] This invention concerns a potent, orally active inhibitor, ponatinib ("compound 1") and pharmaceutical compositions and uses thereof A very promising pharmacological profile of compound 1 has taken shape, based on biochemical testing, cell-based experiments, animal studies and results to date from human clinical studies.
[0011] As disclosed in further detail below, compound 1 is an orally active multi-targeted kinase inhibitor. It is the most potent BCR-ABL inhibitor yet described and the first pan-BCR-ABL inhibitor able to inhibit all known mutant forms of the target, including the currently untreatable T315I mutant that leads to resistance to other drugs. In a phase 1 clinical trial, it demonstrated an attractive safety profile and substantial antileukemic activity in patients with refractory hematological cancers (including a majority of patients with CML and Ph.sup.+ ALL), including patients in which dasatinib and nilotinib are not effective.
[0012] The pharmacokinetic and pharmacodynamic characteristics of compound 1, representing the sum of its kinase inhibitory activities, absorption, distribution, metabolism and excretion behavior in the body, are the characteristics of an orally bioavailable compound capable of achieving concentrations effective for inhibiting a targeted kinase, and in the case of BCR-ABL, for suppressing the outgrowth of cells expressing resistant mutants. The attractive safety profile to date reflects success in achieving those objectives without undue unintended inhibition of kinase activity required for normal functions.
[0013] The significance of that selectivity and safety profile is underscored by the potent activity of compound 1 in inhibiting a range of kinases beyond BCR-ABL and its mutants. For example, compound 1 inhibited FLT3, all 4 members of the FGF receptor family, all 3 VEGF receptors, the angiopoietin receptor TIE2, but was inactive against numerous other kinase classes including the insulin receptor, Aurora kinase, and cyclin-dependent kinase families.
[0014] The invention thus features pharmaceutical compositions and kits containing 3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-(4-((4-methylpiperazin- -1-yl)-methyl)-3-(trifluoromethyl)phenyl)benzamide (compound 1), depicted below:
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