Combining the Allosteric Inhibitor Asciminib with Ponatinib Suppresses Emergence of and Restores Efficacy against Highly Resistant BCR-ABL1 Mutants
Christopher A. Eide,Christopher A. Eide,Matthew S. Zabriskie,Samantha L. Savage Stevens,Orlando Antelope,Nadeem A. Vellore,Hein Than,Anna Reister Schultz,Phillip M. Clair,Amber D. Bowler,Anthony D. Pomicter,Dongqing Yan,Anna V. Senina,Wang Qiang,Wang Qiang,Todd W. Kelley,Philippe Szankasi,Michael Heinrich,Jeffrey W. Tyner,Delphine Rea,Jean Michel Cayuela,Dong-Wook Kim,Cristina E. Tognon,Cristina E. Tognon,Thomas O'Hare,Thomas O'Hare,Brian J. Druker,Brian J. Druker,Michael W. Deininger,Michael W. Deininger +29 more
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TLDR
It is demonstrated that combining asciminib with ATP site TKIs enhances target inhibition and suppression of resistant outgrowth in Ph+ clinical isolates and cell lines and restores ponatinib's effectiveness against currently untreatable compound mutants at clinically achievable concentrations.About:
This article is published in Cancer Cell.The article was published on 2019-10-14 and is currently open access. It has received 120 citations till now. The article focuses on the topics: Ponatinib & Tyrosine-kinase inhibitor.read more
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Kinase drug discovery 20 years after imatinib: progress and future directions.
TL;DR: Cohen et al. as mentioned in this paper reviewed the remarkable progress made over the past 20 years in improving the potency and specificity of small-molecule inhibitors of protein and lipid kinases, resulting in the approval of more than 70 new drugs since imatinib was approved in 2001.
Journal ArticleDOI
Response and Resistance to BCR-ABL1-Targeted Therapies.
TL;DR: Current efforts are focused on identifying therapeutic strategies to drive deeper molecular responses, enabling more patients to attempt TKI discontinuation, and driving disease burden below the detection limit for a greater number of patients.
Journal ArticleDOI
The leukaemia stem cell: similarities, differences and clinical prospects in CML and AML.
TL;DR: Many of the similarities and differences that exist between leukaemia stem cells in CML and AML are reviewed and the therapeutic strategies that could be used to eradicate them are examined.
Journal ArticleDOI
A Phase 3, Open-Label, Randomized Study of Asciminib, a STAMP Inhibitor, vs Bosutinib in CML After ≥2 Prior TKIs
Delphine Rea,Michael J. Mauro,Carla Boquimpani,Yosuke Minami,Elza Lomaia,Sergey Voloshin,Anna G. Turkina,Dong-Wook Kim,Jane F. Apperley,Andre Abdo,Laura Fogliatto,Dennis Dong Hwan Kim,Philipp le Coutre,Susanne Saussele,Mario Annunziata,Timothy P. Hughes,Naeem Chaudhri,Koji Sasaki,Lynette Chee,Valentín García-Gutiérrez,Jorge E. Cortes,Paola Aimone,Alex Allepuz,Sara Quenet,Véronique Bédoucha,Andreas Hochhaus +25 more
TL;DR: The study showed a superior efficacy of asciminib compared with that of bosutinib, together with a favorable safety profile, which support the use of ascIMinib as a new therapy in patients with CML-CP who are resistant or intolerant to ≥2 prior TKIs.
Journal ArticleDOI
PI3K inhibitors: review and new strategies
TL;DR: The search is on for effective specific inhibitors for PI3Kα mutants and the results obtained so far have been limited to drugs that bind to the EMT domain and have shown high specificity towards EMTs.
References
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Journal ArticleDOI
Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification
Mercedes E. Gorre,Mansoor Mohammed,Katharine Ellwood,Nicholas C. Hsu,Ron Paquette,P. Nagesh Rao,Charles L. Sawyers +6 more
TL;DR: It is found that drug resistance is associated with the reactivation of BCR-ABL signal transduction in all cases examined and a strategy for identifying inhibitors of STI-571 resistance is suggested.
Journal ArticleDOI
Multiple BCR-ABL kinase domain mutations confer polyclonal resistance to the tyrosine kinase inhibitor imatinib (STI571) in chronic phase and blast crisis chronic myeloid leukemia
Neil P. Shah,John Nicoll,Bhushan Nagar,Mercedes E. Gorre,Ronald Paquette,John Kuriyan,John Kuriyan,Charles L. Sawyers +7 more
TL;DR: Through sequencing analysis of blood or bone marrow samples from patients with chronic myeloid leukemia, BCR-ABL kinase domain mutations in 29 of 32 patients whose disease relapsed after an initial response to the tyrosine kinase inhibitor imatinib are identified.
Journal ArticleDOI
Dasatinib in Imatinib-Resistant Philadelphia Chromosome–Positive Leukemias
Moshe Talpaz,Neil P. Shah,Hagop M. Kantarjian,Nicholas J. Donato,John Nicoll,Ron Paquette,Jorge E. Cortes,Susan O'Brien,Claude Nicaise,Eric Bleickardt,M. Anne Blackwood-Chirchir,Vishwanath Iyer,Tai-Tsang Chen,Fei Huang,Arthur P. DeCillis,Charles L. Sawyers,Charles L. Sawyers +16 more
TL;DR: Dasatinib induces hematologic and cytogenetic responses in patients with CML or Ph-positive ALL who cannot tolerate or are resistant to imatinib, which is effective in Philadelphia chromosome-positive leukemias but relapse occurs.
Journal ArticleDOI
Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL.
Hagop M. Kantarjian,Francis J. Giles,Lydia Wunderle,Kapil N. Bhalla,Susan O'Brien,Barbara Wassmann,Chiaki Tanaka,Paul W. Manley,Patricia Rae,William Mietlowski,Kathy Bochinski,Andreas Hochhaus,James D. Griffin,Dieter Hoelzer,Maher Albitar,Margaret Dugan,Jorge E. Cortes,Leila Alland,Oliver G. Ottmann +18 more
TL;DR: Nilotinib has a relatively favorable safety profile and is active in imatinib-resistant CML, and common adverse events were myelosuppression, transient indirect hyperbilirubinemia, and rashes.
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.
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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