Journal ArticleDOI
Design and synthesis of tetrahydropyridothieno[2,3-d]pyrimidine scaffold based epidermal growth factor receptor (EGFR) kinase inhibitors: the role of side chain chirality and Michael acceptor group for maximal potency.
Chia Hsien Wu,Mohane Selvaraj Coumar,Chang Ying Chu,Wen-Hsing Lin,Yi-Rong Chen,Chiung-Tong Chen,Hui Yi Shiao,Shaik Rafi,Sing Yi Wang,Hui Hsu,Chun Hwa Chen,Chun Yu Chang,Teng Yuan Chang,Tzu Wen Lien,Ming Yu Fang,Kai-Chia Yeh,Ching Ping Chen,Teng Kuang Yeh,Su Huei Hsieh,John T.A. Hsu,Chun-Chen Liao,Chun-Chen Liao,Yu-Sheng Chao,Hsing Pang Hsieh +23 more
TLDR
HTS hit 7 was modified through hybrid design strategy to introduce a chiral side chain followed by introduction of Michael acceptor group to obtain potent EGFR kinase inhibitors 11 and 19, which inhibited gefitinib-resistant double mutant (DM, T790M/L858R) EGFRKinase at nanomolar concentration.Abstract:
HTS hit 7 was modified through hybrid design strategy to introduce a chiral side chain followed by introduction of Michael acceptor group to obtain potent EGFR kinase inhibitors 11 and 19. Both 11 and 19 showed over 3 orders of magnitude enhanced HCC827 antiproliferative activity compared to HTS hit 7 and also inhibited gefitinib-resistant double mutant (DM, T790M/L858R) EGFR kinase at nanomolar concentration. Moreover, treatment with 19 shrinked tumor in nude mice xenograft model.read more
Citations
More filters
Journal ArticleDOI
Irreversible Protein Kinase Inhibitors: Balancing the Benefits and Risks
Tjeerd Barf,Allard Kaptein +1 more
TL;DR: The therapeutic applicability or the success of irreversible binding kinase inhibitors is dependent on whether or not the covalent bond can be confined solely to the protein kinase of interest.
Patent
Phosphorous derivatives as kinase inhibitors
Yihan Wang,Wei-Sheng Huang,Shuangying Liu,William C. Shakespeare,R. Mathew Thomas,Jiwei Qi,Feng Li,Xiaotian Zhu,Anna Kohlmann,David C. Dalgarno,Jan Antoinette C. Romero,Dong Zou +11 more
TL;DR: In this paper, the authors present compounds of the general formula (I) in which the variable groups are as defined herein, and to their preparation and use, as well as their extraction and use.
Journal ArticleDOI
Structure-Based Virtual Screening Approach for Discovery of Covalently Bound Ligands
TL;DR: CovDock-VS is the first fully automated tool for efficient virtual screening of covalent inhibitors and can handle multiple chemical reactions within the same library, only requiring a generic SMARTS-based predefinition of the reaction.
Journal ArticleDOI
CovalentDock: Automated covalent docking with parameterized covalent linkage energy estimation and molecular geometry constraints
TL;DR: A new covalent docking package, the CovalentDock, built on the top of the source code of Autodock, which is compatible with existing scoring functions used in docking, while handling the molecular geometry constrains of the covalENT linkage with special atom types and directional grid maps.
Journal ArticleDOI
Structural basis for the altered drug sensitivities of non-small cell lung cancer-associated mutants of human epidermal growth factor receptor.
Shingo Yoshikawa,Mutsuko Kukimoto-Niino,Lorien J. Parker,Noriko Handa,Takaho Terada,Fujimoto T,Yumiko Terazawa,Motoaki Wakiyama,Masanao Sato,Satoshi Sano,Tomoyuki Kobayashi,Tetsuo Tanaka,Lirong Chen,Zhi-Jie Liu,Zhi-Jie Liu,Bi-Cheng Wang,Mikako Shirouzu,Seiji Kawa,Seiji Kawa,Kentaro Semba,Tadashi Yamamoto,Tadashi Yamamoto,Shigeyuki Yokoyama +22 more
TL;DR: Structural analyses provide a structural basis for the altered drug sensitivities caused by distinct NSCLC-associated EGFR mutations and support the hypothesis that the expansion of the active-site cleft results in enhanced gefitinib sensitivity.
References
More filters
Journal ArticleDOI
EGFR Mutation and Resistance of Non–Small-Cell Lung Cancer to Gefitinib
Susumu Kobayashi,Titus J. Boggon,Tajhal Dayaram,Pasi A. Jänne,Olivier Kocher,Matthew Meyerson,Bruce E. Johnson,Michael J. Eck,Daniel G. Tenen,Balazs Halmos,Balazs Halmos +10 more
TL;DR: In this paper, the authors reported the case of a patient with EGFR-mutant, gefitinib-responsive, advanced non-small-cell lung cancer who had a relapse after two years of complete remission.
Journal ArticleDOI
Epidermal growth factor receptor mutations in lung cancer
TL;DR: 'oncogenic shock' is described as a mechanistic explanation for the apoptosis that follows the acute treatment of susceptible cells with kinase inhibitors, essential to the successful use of targeted therapies in common epithelial cancers.
Journal ArticleDOI
EGFR Antagonists in Cancer Treatment
TL;DR: The mechanisms of action of EGFR inhibitors, their anticancer activity, and clinical issues concerning their use in the treatment of patients with cancer are discussed.
Journal ArticleDOI
The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP
Cai-Hong Yun,Kristen E. Mengwasser,Angela V. Toms,Michele S. Woo,Heidi Greulich,Heidi Greulich,Kwok-Kin Wong,Kwok-Kin Wong,Matthew Meyerson,Matthew Meyerson,Michael J. Eck +10 more
TL;DR: It is concluded that the T790M mutation is a “generic” resistance mutation that will reduce the potency of any ATP-competitive kinase inhibitor and that irreversible inhibitors overcome this resistance simply through covalent binding, not as a result of an alternative binding mode.
Journal ArticleDOI
BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models.
Daizong Li,Lauren Ambrogio,Lauren Ambrogio,Takeshi Shimamura,Shigeto Kubo,Masaya Takahashi,Lucian R. Chirieac,Robert F. Padera,Geoffrey I. Shapiro,Anke Baum,Frank Himmelsbach,Wolfgang J. Rettig,Matthew Meyerson,Matthew Meyerson,F. Solca,Heidi Greulich,Heidi Greulich,K-K Wong +17 more
TL;DR: It is shown that BIBW2992, an anilino-quinazoline designed to irreversibly bind EGFR and HER2, potently suppresses the kinase activity of wild-type and activated EGFRand HER2 mutants, including erlotinib-resistant isoforms.