ARIAD’s AP24534 Featured in Cancer Cell Publication as a Potential First-in-Class Pan BCR-ABL Inhibitor
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ARIAD Pharmaceuticals, Inc. has announced that the scientific journal, Cancer Cell, has published a comprehensive paper describing the design and preclinical characterization of AP24534, ARIAD’s investigational, multi-targeted kinase inhibitor.
The paper, “AP24534, a Pan-BCR-ABL Inhibitor for Chronic Myeloid Leukemia, Potently Inhibits the T315I Mutant and Overcomes Mutation-Based Resistance,” is co-authored by scientists from ARIAD, and collaborating investigators from the Oregon Health & Science University Knight Cancer Institute and the Howard Hughes Medical Institute.
The publication describes for the first time the chemical structure of AP24534 and its activity against all known BCR-ABL mutants, including the T315I mutant that is resistant to currently marketed therapies for chronic myeloid leukemia (CML).
The paper provides a comprehensive description of the activity of AP24534 in a range of established cell-based and animal models of CML. AP24534 was discovered by ARIAD scientists and is now in a Phase 1 dose-escalating clinical trial in patients with refractory CML, acute myeloid leukemia (AML) and other hematological malignancies.
“These data support the ongoing clinical study of AP24534 to develop a potential much-needed treatment option for patients with resistant mutations such as T315I, that could complement the currently available tyrosine kinase inhibitors,” said Timothy P. Clackson, Ph.D., senior vice president and chief scientific officer at ARIAD and senior author of the paper. “Longer term, a pan-BCR-ABL inhibitor such as AP24534 may offer important advantages by minimizing the development of mutation-based drug resistance.”
Treatment with BCR-ABL inhibitors is initially effective in most patients with CML but can result in the emergence of BCR-ABL mutations that confer drug resistance over time. In a preclinical experiment featured in the publication, even when studied in modest concentrations, AP24534 completely suppressed the emergence of resistant mutants.
This finding is in contrast to results obtained with other BCR-ABL inhibitors previously profiled in this in vitro assay. This resistance profiling method has successfully predicted the specific mutations that confer clinical resistance to marketed CML therapies imatinib (Gleevec?), dasatinib (Sprycel?), and nilotinib (Tasigna?).
“We specifically designed AP24534 as a pan-BCR-ABL inhibitor and its novel profile distinguishes it from all currently available therapies for CML,” added Dr. Clackson. “This preclinical work supports the ongoing clinical evaluation of AP24534 in a broad set of CML patients with many different BCR-ABL mutations, including the T315I mutation.”
AP24534 is a product of ARIAD’s structure-based drug design platform. ARIAD scientists first determined the structure of the T315I mutant of BCR-ABL to discover how the mutation alters the drug binding site. A unique chemical linker was then designed into the AP24534 structure to accommodate the mutation, allowing potent inhibition of this and all other mutants tested.
The paper in Cancer Cell is the culmination of a productive, multi-year collaboration between the ARIAD and Oregon groups to characterize the properties and potential of AP24534. Brian Druker, M.D., director of the Oregon Health & Science University Knight Cancer Institute, Howard Hughes Medical Institute Investigator and JELD-WEN Chair of Leukemia Research at OHSU, is a senior author on the paper.
The paper, “AP24534, a Pan-BCR-ABL Inhibitor for Chronic Myeloid Leukemia, Potently Inhibits the T315I Mutant and Overcomes Mutation-Based Resistance,” is co-authored by scientists from ARIAD, and collaborating investigators from the Oregon Health & Science University Knight Cancer Institute and the Howard Hughes Medical Institute.
The publication describes for the first time the chemical structure of AP24534 and its activity against all known BCR-ABL mutants, including the T315I mutant that is resistant to currently marketed therapies for chronic myeloid leukemia (CML).
The paper provides a comprehensive description of the activity of AP24534 in a range of established cell-based and animal models of CML. AP24534 was discovered by ARIAD scientists and is now in a Phase 1 dose-escalating clinical trial in patients with refractory CML, acute myeloid leukemia (AML) and other hematological malignancies.
“These data support the ongoing clinical study of AP24534 to develop a potential much-needed treatment option for patients with resistant mutations such as T315I, that could complement the currently available tyrosine kinase inhibitors,” said Timothy P. Clackson, Ph.D., senior vice president and chief scientific officer at ARIAD and senior author of the paper. “Longer term, a pan-BCR-ABL inhibitor such as AP24534 may offer important advantages by minimizing the development of mutation-based drug resistance.”
Treatment with BCR-ABL inhibitors is initially effective in most patients with CML but can result in the emergence of BCR-ABL mutations that confer drug resistance over time. In a preclinical experiment featured in the publication, even when studied in modest concentrations, AP24534 completely suppressed the emergence of resistant mutants.
This finding is in contrast to results obtained with other BCR-ABL inhibitors previously profiled in this in vitro assay. This resistance profiling method has successfully predicted the specific mutations that confer clinical resistance to marketed CML therapies imatinib (Gleevec?), dasatinib (Sprycel?), and nilotinib (Tasigna?).
“We specifically designed AP24534 as a pan-BCR-ABL inhibitor and its novel profile distinguishes it from all currently available therapies for CML,” added Dr. Clackson. “This preclinical work supports the ongoing clinical evaluation of AP24534 in a broad set of CML patients with many different BCR-ABL mutations, including the T315I mutation.”
AP24534 is a product of ARIAD’s structure-based drug design platform. ARIAD scientists first determined the structure of the T315I mutant of BCR-ABL to discover how the mutation alters the drug binding site. A unique chemical linker was then designed into the AP24534 structure to accommodate the mutation, allowing potent inhibition of this and all other mutants tested.
The paper in Cancer Cell is the culmination of a productive, multi-year collaboration between the ARIAD and Oregon groups to characterize the properties and potential of AP24534. Brian Druker, M.D., director of the Oregon Health & Science University Knight Cancer Institute, Howard Hughes Medical Institute Investigator and JELD-WEN Chair of Leukemia Research at OHSU, is a senior author on the paper.
