Journal ArticleDOI
Crystal Structures of Anaplastic Lymphoma Kinase in Complex with ATP Competitive Inhibitors.
R.T. Bossi,M.B. Saccardo,Elena Ardini,Maria Menichincheri,Luisa Rusconi,Paola Magnaghi,Paolo Orsini,N. Avanzi,A.L. Borgia,M. Nesi,T. Bandiera,Gianpaolo Fogliatto,J.A. Bertrand +12 more
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TLDR
Analysis of the crystal structures of the unphosphorylated human ALK kinase domain in complex with the ATP competitive ligands PHA-E429 and NVP-TAE684 provides valuable information concerning the specific characteristics of the ALK active site as well as giving indications about how to obtain selective ALK inhibitors.Abstract:
Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase involved in the development of several human cancers and, as a result, is a recognized target for the development of small-molecule in...read more
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Journal ArticleDOI
Mechanisms of Acquired Crizotinib Resistance in ALK-Rearranged Lung Cancers
Ryohei Katayama,Alice T. Shaw,Alice T. Shaw,Tahsin M. Khan,Tahsin M. Khan,Mari Mino-Kenudson,Benjamin Solomon,Balazs Halmos,Nicholas A. Jessop,John C. Wain,Alan Tien Yeo,Cyril H. Benes,Lisa Drew,Jamal Carlos Saeh,Katherine Crosby,Lecia V. Sequist,A. John Iafrate,Jeffrey A. Engelman +17 more
TL;DR: Findings from a series of lung cancer patients with acquired resistance to the ALK TKI crizotinib reinforce the need to tailor therapeutic strategies to the specific underlying drug resistance mechanisms in the tumors to improve clinical outcomes.
Journal ArticleDOI
EML4-ALK Mutations in Lung Cancer That Confer Resistance to ALK Inhibitors
Young Lim Choi,Manabu Soda,Yoshihiro Yamashita,Toshihide Ueno,Junpei Takashima,Takahiro Nakajima,Yasushi Yatabe,Kengo Takeuchi,Toru Hamada,Hidenori Haruta,Yuichi Ishikawa,Hideki Kimura,Tetsuya Mitsudomi,Yoshiro Tanio,Hiroyuki Mano +14 more
TL;DR: The discovery of two secondary mutations within the kinase domain of EML4-ALK in tumor cells isolated from a patient during the relapse phase of treatment with an ALK inhibitor are reported.
Journal ArticleDOI
A Novel ALK Secondary Mutation and EGFR Signaling Cause Resistance to ALK Kinase Inhibitors
Takaaki Sasaki,Jussi Koivunen,Atsuko Ogino,Masahiko Yanagita,Sarah Nikiforow,Wei Zheng,Christopher S. Lathan,J. Paul Marcoux,Jinyan Du,Katsuhiro Okuda,Marzia Capelletti,Takeshi Shimamura,Dalia Ercan,Magda Stumpfova,Yun Xiao,Stanislawa Weremowicz,Mohit Butaney,Stephanie Heon,Keith D. Wilner,James G. Christensen,Michael J. Eck,Kwok-Kin Wong,Neal I. Lindeman,Nathanael S. Gray,Scott J. Rodig,Pasi A. Jänne +25 more
TL;DR: Two mechanisms of ALK TKI resistance identified from a crizotinib-treated non-small cell lung cancer (NSCLC) patient and in a cell line generated from the resistant tumor (DFCI076) as well as from studying a resistant version of the ALk TKI (TAE684)-sensitive H3122 cell line.
Journal ArticleDOI
CH5424802, a Selective ALK Inhibitor Capable of Blocking the Resistant Gatekeeper Mutant
Hiroshi Sakamoto,Toshiyuki Tsukaguchi,Sayuri Hiroshima,Tatsushi Kodama,Takamitsu Kobayashi,Takaaki A. Fukami,Nobuhiro Oikawa,Takuo Tsukuda,Nobuya Ishii,Yuko Aoki +9 more
TL;DR: CH5424802 is identified, a potent, selective, and orally available ALK inhibitor with a unique chemical scaffold, showing preferential antitumor activity against cancers with gene alterations of ALK, such as nonsmall cell lung cancer (NSCLC) cells expressing EML4-ALK fusion and anaplastic large-cell lymphoma (ALCL) cellsExpressing NPM-alk fusion in vitro and in vivo.
Journal ArticleDOI
Mechanistic insight into ALK receptor tyrosine kinase in human cancer biology
Bengt Hallberg,Ruth H. Palmer +1 more
TL;DR: The current understanding of ALK function in human cancer and the implications for tumour treatment are discussed.
References
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Journal ArticleDOI
Phaser crystallographic software
Airlie J. McCoy,Ralf W. Grosse-Kunstleve,Paul D. Adams,Martyn Winn,Laurent C. Storoni,Randy J. Read +5 more
TL;DR: A description is given of Phaser-2.1: software for phasing macromolecular crystal structures by molecular replacement and single-wavelength anomalous dispersion phasing.
Journal ArticleDOI
Identification of the transforming EML4–ALK fusion gene in non-small-cell lung cancer
Manabu Soda,Young Lim Choi,Munehiro Enomoto,Shuji Takada,Yoshihiro Yamashita,Shunpei Ishikawa,Shin-ichiro Fujiwara,Hideki Watanabe,Kentaro Kurashina,Hisashi Hatanaka,Masashi Bando,Shoji Ohno,Yuichi Ishikawa,Hiroyuki Aburatani,Toshiro Niki,Yasunori Sohara,Yukihiko Sugiyama,Hiroyuki Mano +17 more
TL;DR: It is shown that a small inversion within chromosome 2p results in the formation of a fusion gene comprising portions of the echinoderm microtubule-associated protein-like 4 (EML4) gene and the anaplastic lymphoma kinase (ALK) gene in non-small-cell lung cancer (NSCLC) cells.
Journal ArticleDOI
ESPript: Analysis of multiple sequence alignments in PostScript
TL;DR: The program ESPript allows the rapid visualization, via PostScript output, of sequences aligned with popular programs such as CLUSTAL-W or GCG PILEUP, and can read secondary structure files to produce a synthesis of both sequence and structural information.
Journal ArticleDOI
Staurosporine, a potent inhibitor of phospholipid/Ca++dependent protein kinase.
TL;DR: Staurosporine, microbial alkaloid which has been known to have antifungal activity was found to inhibit markedly phospholipid/Ca++dependent protein kinase (protein kinase C) from rat brain, with an IC50 value of 2.7 nM.
Journal ArticleDOI
Fusion of a Kinase Gene, ALK, to a Nucleolar Protein Gene, NPM, in Non-Hodgkin's Lymphoma
Stephan W. Morris,Mark N. Kirstein,Marcus B. Valentine,KG Dittmer,KG Dittmer,David N. Shapiro,David N. Shapiro,D. L. Saltman,AT Look,AT Look +9 more
TL;DR: In the predicted hybrid protein, the amino terminus of nucleophosmin (NPM) is linked to the catalytic domain of anaplastic lymphoma kinase (ALK), and unscheduled expression of the truncated ALK may contribute to malignant transformation in these lymphomas.
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