Binding modes of 6,7 di-substituted 4-anilinoquinoline-3-carbonitriles to EGFR

Akula, Nagaraju; Bhalla, Jag; Sridhar, Jayalakshmi; Pattabiraman, Nagarajan

doi:10.1016/j.bmcl.2004.04.080

Cited by 4 publications

(3 citation statements)

References 14 publications

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“…The IC 50 values for such inhibitors should depend on the extent to which the covalent interaction has occurred. In addition, we have suggested, and it has been recapitulated by others, that the IC 50 values could arise from two components, one reflecting reversible binding and another reflecting the subsequent covalent binding. One would therefore expect that the IC 50 values would be time-dependent insofar as an inhibitor that reacts more slowly with the enzyme, or does not react at all, would be expected to have a higher IC 50 value.…”

Section: Resultssupporting

confidence: 62%

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Optimization of 6,7-Disubstituted-4-(arylamino)quinoline-3-carbonitriles as Orally Active, Irreversible Inhibitors of Human Epidermal Growth Factor Receptor-2 Kinase Activity

et al. 2005

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A series of new 6,7-disubstituted-4-(arylamino)quinoline-3-carbonitrile derivatives that function as irreversible inhibitors of human epidermal growth factor receptor-2 (HER-2) and epidermal growth factor receptor (EGFR) kinases have been prepared. These compounds demonstrated enhanced activities for inhibiting HER-2 kinase and the growth of HER-2 positive cells compared to our EGFR kinase inhibitor 86 (EKB-569). Three synthetic routes were used to prepare these compounds. They were prepared mostly by acylation of 6-amino-4-(arylamino)quinoline-3-carbonitriles with unsaturated acid chlorides or by amination of 4-chloro-6-(crotonamido)quinoline-3-carbonitriles with monocyclic or bicyclic anilines. The third route was developed to prepare a key intermediate, 6-acetamido-4-chloroquinoline-3-carbonitrile, that involved a safer cyclization step. We show that attaching a large lipophilic group at the para position of the 4-(arylamino) ring results in improved potency for inhibiting HER-2 kinase. We also show the importance of a basic dialkylamino group at the end of the Michael acceptor for activity, due to intramolecular catalysis of the Michael addition. This, along with improved water solubility, resulted in compounds with enhanced biological properties. We present molecular modeling results consistent with the proposed mechanism of inhibition. Binding studies of one compound, 25o (C-14 radiolabeled), showed that it binds irreversibly to HER-2 protein in BT474 cells. Furthermore, it demonstrated excellent oral activity, especially in HER-2 overexpressing xenografts. Compound 25o (HKI-272) was selected for further studies and is currently in phase I clinical trials for the treatment of cancer.

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Section: Resultssupporting

confidence: 62%

“…A paper describing a study of the binding modes of 6,7-disubstituted 4-anilinoquinoline-3-carbonitriles to the closely related EGFR kinase appeared recently …”

Section: Molecular Modelingmentioning

confidence: 99%

Optimization of 6,7-Disubstituted-4-(arylamino)quinoline-3-carbonitriles as Orally Active, Irreversible Inhibitors of Human Epidermal Growth Factor Receptor-2 Kinase Activity

et al. 2005

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“…The structure and data of 4‐aminoquinoline analogues are shown in Fig . and Table . There are two similar compounds ( Fig .…”

Section: Second‐generation Irreversible Egfr Tkismentioning

confidence: 87%

Recent Development of the Second and Third Generation Irreversible Epidermal Growth Factor Receptor Inhibitors

Wang

2017

Chemistry & Biodiversity

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Recent reports suggested that essential directions for new lung cancer, breast carcinoma therapies, as well as the roomier realm of targeted cancer therapies were provided through targeting the epidermal growth factor receptor (EGFR). Patients who carrying non-small cell lung carcinoma (NSCLC) with activating mutations in EGFR initially respond well to the EGFR inhibitors erlotinib and gefitinib, which were located the active site of the EGFR kinase and designed to act as competitive inhibitors of combining with the ATP. However, patients who were treated with the erlotinib and gefitinib will relapse because of the emergence of drug-resistant mutations, with T790M mutations accounting for approximately 60% of all resistance. In order to overcome drug resistance, Pharmaceutical chemistry experts recently devoted great endeavors to the development of second-generation irreversible selective inhibitors which covalently modify Cys797 or Cys773 at the ATP binding cleft. Nevertheless, these inhibitors have not reached ideal effect of experts in patients with T790M positive mutation and apparently because of the dose-limiting toxicities associated with inhibition of wild type EGFR. A novel class of 'third generation' EGFR TKIs have been developed that is sensitising and T790M mutant-specific whilst sparing WT EGFR, representing a significant breakthrough in the treatment in NSCLC patients with acquired resistance harboring these genotypes. Herein, we provides an overview of the second and third generation inhibitors currently approved, in clinical trial and also encompasses novel structures of discovery. This review mainly focuses on drug resistance, their mechanisms of action, development of structure-activity relationships and binding modes.

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3D-QSAR studies on c-Src kinase inhibitors and docking analyses of a potent dual kinase inhibitor of c-Src and c-Abl kinases

Thaimattam

Daga

Banerjee

et al. 2005

Bioorganic & Medicinal Chemistry

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Binding modes of 6,7 di-substituted 4-anilinoquinoline-3-carbonitriles to EGFR

Cited by 4 publications

References 14 publications

Optimization of 6,7-Disubstituted-4-(arylamino)quinoline-3-carbonitriles as Orally Active, Irreversible Inhibitors of Human Epidermal Growth Factor Receptor-2 Kinase Activity

Optimization of 6,7-Disubstituted-4-(arylamino)quinoline-3-carbonitriles as Orally Active, Irreversible Inhibitors of Human Epidermal Growth Factor Receptor-2 Kinase Activity

Recent Development of the Second and Third Generation Irreversible Epidermal Growth Factor Receptor Inhibitors

3D-QSAR studies on c-Src kinase inhibitors and docking analyses of a potent dual kinase inhibitor of c-Src and c-Abl kinases

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