| Ponatinib | |
|---|---|
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3-(2-Imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]benzamide |
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Other names
AP24534 |
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| Identifiers | |
| CAS number | 943319-70-8 |
| ChemSpider | 24747381 |
| Jmol-3D images | Image 1 |
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| Properties | |
| Molecular formula | C29H27F3N6O |
| Molar mass | 532.56 g mol−1 |
| Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa) | |
| Infobox references | |
Ponatinib (AP24534) is an experimental oral drug candidate for the treatment of chronic myeloid leukemia (CML) and Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL). It is a multi-targeted tyrosine-kinase inhibitor.[1] Some forms of CML, those that have the T315I mutation, are resistant to current therapies such as imatinib. Ponatinib has been designed to be effective against these types of tumors.[2]
Ponatinib is currently in Phase II clinical trials in patients with resistant or intolerant CML and Ph+ ALL. The PACE (Ponatinb Ph+ ALL and CML Evaluation) trial started enrolling patients in September 2010 and is designed to provide definitive clinical data for regulatory approval in this setting. ARIAD Pharmaceuticals, the company that is developing ponatinib, said it expects full enrollment of the PACE trial in the third quarter of 2011.
The primary target for ponatinib is BCR-ABL, an abnormal tyrosine kinase that is the hallmark of CML and Ph+ ALL. CML is characterized by an excessive and unregulated production of white blood cells by the bone marrow due to a genetic abnormality that produces the BCR-ABL protein. After a chronic phase of production of too many white blood cells, CML typically evolves to more aggressive phases such as accelerated or blast crisis. Ph+ ALL is a subtype of acute lymphoblastic leukemia that carries the Ph+ chromosome that produces BCR-ABL. It has a more aggressive course than CML and is often treated with a combination of chemotherapy and tyrosine kinase inhibitors. Because both of these diseases express the BCR-ABL protein, this would render them potentially susceptible to treatment with ponatinib. BCR-ABL is detected in 95% of patients with CML. Patients with CML currently receive front line therapies nilotinib and/or dasatinib though 22-33% of patients discontinue therapy by two years due to adverse events, treatment failure and other causes.
Ponatinib was designed using ARIAD’s computational and structure-based drug design platform to inhibit the enzymatic activity of BCR-ABL with very high potency and broad specificity. Ponatinib was intended to target not only native BCR-ABL, but also its isoforms that carry mutations that confer resistance to treatment with existing tyrosine kinase inhibitors, including especially the T315I mutation for which no effective therapy exists.[3]
At the 2010 annual meeting of the American Society of Hematology, ARIAD announced from a Phase I study of ponatinib in patients with resistant and refractory chronic myeloid leukemia (CML) and Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL). The study demonstrated that in chronic-phase CML patients treated with ponatinib, 66 percent of patients in the trial achieved a major cytogenetic response, including 100 percent of patients who also had a T315I mutation.