Journal ArticleDOI
Discovery of N-(5-((5-chloro-4-((2-(isopropylsulfonyl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(4-methyl-1,4-diazepan-1-yl)phenyl)acrylamide (CHMFL-ALK/EGFR-050) as a potent ALK/EGFR dual kinase inhibitor capable of overcoming a variety of ALK/EGFR associated drug resistant mutants in NSCLC
Yongfei Chen,Jiaxin Wu,Aoli Wang,Ziping Qi,Taoshan Jiang,Cheng Chen,Fengming Zou,Chen Hu,Wei Wang,Hong Wu,Zhenquan Hu,Wenchao Wang,Beilei Wang,Li Wang,Tao Ren,Shanchun Zhang,Qingsong Liu,Jing Liu +17 more
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TLDR
A highly potent EGFR/ALK dual kinase inhibitor compound 18 (CHMFL-ALK/EGFR-050), which potently inhibited EGFR L858R, del 19 and T790M mutants as well as EML4-ALK, R1275Q, L1196M, F1174L and C1156Y mutants biochemically and significantly suppressed the tumor growth in H1975 cell inoculated xenograft model.About:
This article is published in European Journal of Medicinal Chemistry.The article was published on 2017-10-20. It has received 37 citations till now. The article focuses on the topics: ALK inhibitor & T790M.read more
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The function and therapeutic targeting of anaplastic lymphoma kinase (ALK) in non-small cell lung cancer (NSCLC)
TL;DR: Several new approaches aim to overcome the various mechanisms of resistance that develop in ALK-positive NSCLC including the knowledge-based alternate and successive use of different ALK inhibitors, as well as combined therapies targeting ALK plus alternative signaling pathways.
Journal ArticleDOI
Design, synthesis and anticancer evaluation of thieno[2,3-d]pyrimidine derivatives as dual EGFR/HER2 inhibitors and apoptosis inducers
TL;DR: The synthesized thieno[2,3-d]pyrimidine derivatives as an EGFR and HER2 tyrosine kinase inhibitors and the results indicated that this compound arrests G2/M phase of the cell cycle and it is a good apoptotic agent.
Journal ArticleDOI
Design, synthesis and anticancer evaluation of 1H-pyrazolo[3,4-d]pyrimidine derivatives as potent EGFRWT and EGFRT790M inhibitors and apoptosis inducers
Ahmed A. Gaber,Ashraf H. Bayoumi,Ahmed El-Morsy,Farag F. Sherbiny,Ahmed B.M. Mehany,Ibrahim H. Eissa +5 more
TL;DR: Results indicated that the most active compound 18d was selected for further studies regarding to its effects on cell cycle progression and induction of apoptosis in the HepG2 cell line and indicated that this compound is good apoptotic agent and arrests G0/G1and G2/M phases of cell cycle.
Journal ArticleDOI
The next tier of EGFR resistance mutations in lung cancer.
TL;DR: A survey of the diverse landscape of EGFR resistance mechanisms with a focus on new insights into on-target EGFR kinase mutations is presented.
Journal ArticleDOI
Discovery of new pyrimidine-5-carbonitrile derivatives as anticancer agents targeting EGFRWT and EGFRT790M.
Ahmed A. Nasser,Ibrahim H. Eissa,Mohamed R. Oun,Mohamed El-Zahabi,Mohammed S Taghour,Amany Belal,Abdulrahman M. Saleh,Ahmed B.M. Mehany,Hendrik Luesch,Ahmad E. Mostafa,Wael M. Afifi,Wael M. Afifi,James R. Rocca,Hazem A. Mahdy +13 more
TL;DR: Five pyrimidine-5-carbonitrile derivatives synthesized as ATP mimicking tyrosine kinase inhibitors of the epidermal growth factor receptor (EGFR) were found to exhibit moderate antiproliferative activity against the tested cell lines and were more active than the EGFR inhibitor erlotinib.
References
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Journal ArticleDOI
Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib
Thomas J. Lynch,Daphne W. Bell,Raffaella Sordella,Sarada Gurubhagavatula,Ross A. Okimoto,Brian W. Brannigan,Patricia L. Harris,Sara M. Haserlat,Jeffrey G. Supko,Frank G. Haluska,David N. Louis,David C. Christiani,Jeff Settleman,Daniel A. Haber +13 more
TL;DR: A subgroup of patients with non-small-cell lung cancer have specific mutations in the EGFR gene which correlate with clinical responsiveness to the tyrosine kinase inhibitor gefitinib, and these mutations lead to increased growth factor signaling and confer susceptibility to the inhibitor.
Journal ArticleDOI
EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy.
J. Guillermo Paez,Pasi A. Jänne,Pasi A. Jänne,Jeffrey C. Lee,Sean Tracy,Heidi Greulich,Heidi Greulich,Stacey Gabriel,Paula Herman,Frederic J. Kaye,Neal I. Lindeman,Titus J. Boggon,Katsuhiko Naoki,Hidefumini Sasaki,Yoshitaka Fujii,Michael J. Eck,William R. Sellers,William R. Sellers,William R. Sellers,Bruce E. Johnson,Bruce E. Johnson,Matthew Meyerson,Matthew Meyerson +22 more
TL;DR: Results suggest that EGFR mutations may predict sensitivity to gefitinib, and treatment with the EGFR kinase inhibitor gefitsinib causes tumor regression in some patients with NSCLC, more frequently in Japan.
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
EGF receptor gene mutations are common in lung cancers from “never smokers” and are associated with sensitivity of tumors to gefitinib and erlotinib
William Pao,Vincent A. Miller,Maureen F. Zakowski,Jennifer Doherty,Katerina Politi,Inderpal S. Sarkaria,Bhuvanesh Singh,Robert T. Heelan,Valerie W. Rusch,Lucinda Fulton,Elaine R. Mardis,Doris M. Kupfer,Richard K. Wilson,Mark G. Kris,Harold E. Varmus +14 more
TL;DR: Data show that adenocarcinomas from never smokers comprise a distinct subset of lung cancers, frequently containing mutations within the TK domain of EGFR that are associated with gefitinib and erlotinib sensitivity.
Journal ArticleDOI
PROPKA3: Consistent Treatment of Internal and Surface Residues in Empirical pKa Predictions
TL;DR: The rules and parameters for one of the most commonly used empirical pKa predictors, PROPKA, are revised based on better physical description of the desolvation and dielectric response for the protein, and a new and consistent approach to interpolate the description between the previously distinct classifications into internal and surface residues is introduced.
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Helen Y. Zou,Lars R. Engstrom,Qiuhua Li,Melissa West Lu,Ruth W. Tang,Hui Wang,Konstantinos Tsaparikos,Jinwei Wang,Sergei Timofeevski,Dac M. Dinh,Hieu Lam,Justine L. Lam,Shinji Yamazaki,Wenyue Hu,Timothy Affolter,Patrick B. Lappin,Hovhannes J. Gukasyan,Nathan V. Lee,Jennifer M. Tursi,Ted William Johnson,Valeria Fantin,Tod Smeal +21 more