Ponatinib: a novel multi-tyrosine kinase inhibitor against human malignancies.
Fiona H Tan,Tracy L Putoczki,Tracy L Putoczki,Stanley S. Stylli,Stanley S. Stylli,Rodney B. Luwor +5 more
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TLDR
This review focuses on the available data of ponatinib and its molecular targets for treatment in various cancers, with a discussion on the broader potential of this agent in other cancer indications.Abstract:
Human malignancies are often the result of overexpressed and constitutively active receptor and non-receptor tyrosine kinases, which ultimately lead to the mediation of key tumor-driven pathways. Several tyrosine kinases (ie, EGFR, FGFR, PDGFR, VEGFR), are aberrantly activated in most common tumors, including leukemia, glioblastoma, gastrointestinal stromal tumors, non-small-cell lung cancer, and head and neck cancers. Iclusig™ (ponatinib, previously known as AP24534) is an orally active multi-tyrosine kinase inhibitor and is currently approved by the US Food and Drug Administration for patients with chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia, specifically targeting the BCR-ABL gene mutation, T315I. Due to ponatinib's unique multi-targeted characteristics, further studies have demonstrated its ability to target other important tyrosine kinases (FGFR, PDGFR, SRC, RET, KIT, and FLT1) in other human malignancies. This review focuses on the available data of ponatinib and its molecular targets for treatment in various cancers, with a discussion on the broader potential of this agent in other cancer indications.read more
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Journal ArticleDOI
AP24534, a Pan-BCR-ABL Inhibitor for Chronic Myeloid Leukemia, Potently Inhibits the T315I Mutant and Overcomes Mutation-Based Resistance
Thomas O'Hare,Thomas O'Hare,William C. Shakespeare,Xiaotian Zhu,Christopher A. Eide,Christopher A. Eide,Victor M. Rivera,Frank Wang,Lauren T. Adrian,Lauren T. Adrian,Tianjun Zhou,Huang Wei Sheng,Qihong Xu,Chester A. Metcalf,Jeffrey W. Tyner,Marc M. Loriaux,Amie S. Corbin,Amie S. Corbin,Scott Wardwell,Yaoyu Ning,Jeffrey A. Keats,Yihan Wang,Raji Sundaramoorthi,Mathew Thomas,Dong Zhou,Joseph Snodgrass,Lois Commodore,Tomi K. Sawyer,David C. Dalgarno,Michael W. Deininger,Brian J. Druker,Brian J. Druker,Tim Clackson +32 more
TL;DR: Design and preclinical evaluation of AP24534, a potent, orally available multitargeted kinase inhibitor active against T315I and other BCR-ABL mutants, and clinical evaluation ofAP24534 as a pan-BCR-ABl inhibitor for treatment of CML are reported.
Journal ArticleDOI
A Phase 2 Trial of Ponatinib in Philadelphia Chromosome–Positive Leukemias
Jorge E. Cortes,Dong-Kee Kim,Javier Pinilla-Ibarz,P. le Coutre,Ronald Paquette,Charles Chuah,F. E. Nicolini,Jane F. Apperley,Hanna Jean Khoury,Moshe Talpaz,John F. DiPersio,Daniel J. DeAngelo,Elisabetta Abruzzese,Delphine Rea,Michele Baccarani,Martin C. Müller,Carlo Gambacorti-Passerini,Stephane Wong,Stephanie Lustgarten,Victor M. Rivera,Timothy P. Clackson,Christopher D. Turner,Frank G. Haluska,François Guilhot,Michael W. Deininger,Andreas Hochhaus,Timothy P. Hughes,J. M. Goldman,Neil P. Shah,Hagop M. Kantarjian +29 more
TL;DR: Ponatinib had significant antileukemic activity across categories of disease stage and mutation status and were durable; the estimated rate of a sustained major cytogenetic response of at least 12 months was 91%.
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