Cancer cell, 2009-11, Vol.16 (5), p.401-412
- O'Hare, Thomas
- Shakespeare, William C.
- Zhu, Xiaotian
- Eide, Christopher A.
- Rivera, Victor M.
- Wang, Frank
- Adrian, Lauren T.
- Zhou, Tianjun
- Huang, Wei-Sheng
- Xu, Qihong
- Metcalf, Chester A.
- Tyner, Jeffrey W.
- Loriaux, Marc M.
- Corbin, Amie S.
- Wardwell, Scott
- Ning, Yaoyu
- Keats, Jeffrey A.
- Wang, Yihan
- Sundaramoorthi, Raji
- Thomas, Mathew
- Zhou, Dong
- Snodgrass, Joseph
- Commodore, Lois
- Sawyer, Tomi K.
- Dalgarno, David C.
- Deininger, Michael W.N.
- Druker, Brian J.
- Clackson, Tim
2009
Details
- Autor(en) / Beteiligte
- O'Hare, Thomas
- Shakespeare, William C.
- Zhu, Xiaotian
- Eide, Christopher A.
- Rivera, Victor M.
- Wang, Frank
- Adrian, Lauren T.
- Zhou, Tianjun
- Huang, Wei-Sheng
- Xu, Qihong
- Metcalf, Chester A.
- Tyner, Jeffrey W.
- Loriaux, Marc M.
- Corbin, Amie S.
- Wardwell, Scott
- Ning, Yaoyu
- Keats, Jeffrey A.
- Wang, Yihan
- Sundaramoorthi, Raji
- Thomas, Mathew
- Zhou, Dong
- Snodgrass, Joseph
- Commodore, Lois
- Sawyer, Tomi K.
- Dalgarno, David C.
- Deininger, Michael W.N.
- Druker, Brian J.
- Clackson, Tim
- Titel
- AP24534, a Pan-BCR-ABL Inhibitor for Chronic Myeloid Leukemia, Potently Inhibits the T315I Mutant and Overcomes Mutation-Based Resistance
- Ist Teil von
- Cancer cell, 2009-11, Vol.16 (5), p.401-412
- Ort / Verlag
- United States: Elsevier Inc
- Erscheinungsjahr
- 2009
- Link zum Volltext
- Quelle
- Free E-Journal (出版社公開部分のみ）
- Beschreibungen/Notizen
- Inhibition of BCR-ABL by imatinib induces durable responses in many patients with chronic myeloid leukemia (CML), but resistance attributable to kinase domain mutations can lead to relapse and a switch to second-line therapy with nilotinib or dasatinib. Despite three approved therapeutic options, the cross-resistant BCR-ABL T315I mutation and compound mutants selected on sequential inhibitor therapy remain major clinical challenges. We report design and preclinical evaluation of AP24534, a potent, orally available multitargeted kinase inhibitor active against T315I and other BCR-ABL mutants. AP24534 inhibited all tested BCR-ABL mutants in cellular and biochemical assays, suppressed BCR-ABL T315I-driven tumor growth in mice, and completely abrogated resistance in cell-based mutagenesis screens. Our work supports clinical evaluation of AP24534 as a pan-BCR-ABL inhibitor for treatment of CML.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1535-6108eISSN: 1878-3686DOI: 10.1016/j.ccr.2009.09.028Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_2804470
- Format
- –
- Schlagworte
- Abl protein, Animals, Antineoplastic Agents - chemistry, Antineoplastic Agents - pharmacology, BCR protein, Cell Growth Processes - drug effects, Cell Line, Tumor, CHEMBIO, Chronic myeloid leukemia, Crystallography, X-Ray, Fusion protein, Fusion Proteins, bcr-abl - antagonists & inhibitors, Fusion Proteins, bcr-abl - chemistry, Fusion Proteins, bcr-abl - genetics, Fusion Proteins, bcr-abl - metabolism, Humans, HUMDISEASE, Imatinib, Imidazoles - chemistry, Imidazoles - pharmacology, Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy, Leukemia, Myelogenous, Chronic, BCR-ABL Positive - enzymology, Leukemia, Myelogenous, Chronic, BCR-ABL Positive - genetics, Leukemia, Myelogenous, Chronic, BCR-ABL Positive - pathology, Mice, Mice, SCID, Models, Molecular, Mutagenesis, Mutation, Protein Kinase Inhibitors - chemistry, Protein Kinase Inhibitors - pharmacology, Proto-Oncogene Proteins c-abl - antagonists & inhibitors, Proto-Oncogene Proteins c-abl - chemistry, Proto-Oncogene Proteins c-abl - genetics, Proto-Oncogene Proteins c-abl - metabolism, Pyridazines - chemistry, Pyridazines - pharmacology, Signal Transduction - drug effects, Tumors