Design, Synthesis, and Biological Evaluation of Novel Conformationally Constrained Inhibitors Targeting Epidermal Growth Factor Receptor Threonine<sup>790</sup> → Methionine<sup>790</sup> Mutant

Chang, Shaohua; Zhang, Lianwen; Xu, Shilin; Luo, Jinfeng; Lu, Xiaoyun; Zhang, Zhang; Xu, Tianfeng; Liu, Yingxue; Tu, Zhengchao; Xu, Yong; Ren, Xiaomei; Geng, Meiyu; Ding, Jian; Pei, Duanqing; Ding, Ke

doi:10.1021/jm201591k

Cited by 79 publications

(69 citation statements)

References 42 publications

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“…The structure and data of 3,4‐dihydro‐2‐oxopyrimido[4,5‐ d ]pyrimidinyl derivatives are shown in Fig . and Table . WZ4002 potently inhibited the proliferation of the cancer cells or Ba/F3 cells harboring T790M mutated EGFR ( Fig .…”

Section: Third‐generation Irreversible Egfr Tkismentioning

confidence: 81%

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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Section: Third‐generation Irreversible Egfr Tkismentioning

confidence: 81%

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

Wang

2017

Chemistry & Biodiversity

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“…The chlorine of FIIN-3 is within hydrogen-bonding distance of Thr854 in EGFR (and of Ala629, at the same position, in FGFR); this interaction may explain why FIIN-3 showed stronger potency than FIIN-2 against EGFR. The 4-acrylamidobenzyl group of FIIN-3, which is longer than the 3-acrylamidophenyl substituents present in other reported EGFR covalent inhibitors (4,62), provides the flexibility and proper distance for the covalent binding to distinctive cysteines of EGFR and FGFR.…”

Section: Significancementioning

confidence: 98%

Development of covalent inhibitors that can overcome resistance to first-generation FGFR kinase inhibitors

Li¹,

Wang²,

Tanizaki

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

165

132

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The human FGF receptors (FGFRs) play critical roles in various human cancers, and several FGFR inhibitors are currently under clinical investigation. Resistance usually results from selection for mutant kinases that are impervious to the action of the drug or from up-regulation of compensatory signaling pathways. Preclinical studies have demonstrated that resistance to FGFR inhibitors can be acquired through mutations in the FGFR gatekeeper residue, as clinically observed for FGFR4 in embryonal rhabdomyosarcoma and neuroendocrine breast carcinomas. Here we report on the use of a structure-based drug design to develop two selective, next-generation covalent FGFR inhibitors, the FGFR irreversible inhibitors 2 (FIIN-2) and 3 (FIIN-3). To our knowledge, FIIN-2 and FIIN-3 are the first inhibitors that can potently inhibit the proliferation of cells dependent upon the gatekeeper mutants of FGFR1 or FGFR2, which confer resistance to first-generation clinical FGFR inhibitors such as NVP-BGJ398 and AZD4547. Because of the conformational flexibility of the reactive acrylamide substituent, FIIN-3 has the unprecedented ability to inhibit both the EGF receptor (EGFR) and FGFR covalently by targeting two distinct cysteine residues. We report the cocrystal structure of FGFR4 with FIIN-2, which unexpectedly exhibits a "DFG-out" covalent binding mode. The structural basis for dual FGFR and EGFR targeting by FIIN3 also is illustrated by crystal structures of FIIN-3 bound with FGFR4 V550L and EGFR L858R. These results have important implications for the design of covalent FGFR inhibitors that can overcome clinical resistance and provide the first example, to our knowledge, of a kinase inhibitor that covalently targets cysteines located in different positions within the ATP-binding pocket.drug discovery | cancer drug resistance | kinase inhibitor | structure-based drug design R eceptor tyrosine kinases (RTKs) serve as critical sensors of extracellular cues that activate a myriad of intracellular signaling pathways to regulate cell state. There are 58 receptor tyrosine kinases in the human genome, and many have been demonstrated to be constitutively activated through amplification or mutation in particular cancers. The signals emanating from these RTKs, such as epidermal growth factor receptor (EGFR), FGF receptor (FGFR), platelet-derived growth factor receptor (PDGFR), protein kinase Kit (KIT), and protein kinase c-Met (MET), have been pharmacologically proven to be essential to the survival of cancers expressing mutant forms of these proteins. However, rapid resistance to monotherapy with first-generation RTK inhibitors has been universally observed. Resistance typically arises from the emergence of cancer cells expressing mutant forms of RTKs that are impervious to the action of first-generation drugs or from the activation of by-pass signaling mechanisms. Resistance can be overcome by developing new inhibitors that target the mutant RTK directly or target bypass signaling mechanisms. Indeed this approach has been deployed succes...

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“…Additionally, the EGFR‐overexpressing MCF‐7 cell line and SGC‐7901 cell line were also chosen for further biological investigation. All theses cell‐based evaluations were performed using the MTT assay . The test results are summarized in Table .…”

Section: Resultsmentioning

confidence: 99%

Novel Quinazoline Derivatives Bearing Various 4‐Aniline Moieties as Potent EGFR Inhibitors with Enhanced Activity Against NSCLC Cell Lines

et al. 2015

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A class of novel quinazoline derivatives bearing various C-4 aniline moieties was synthesized and biologically evaluated as potent epidermal growth factor receptor (EGFR) inhibitors for intervention of non-small-cell lung cancer (NSCLC). Most of these inhibitors are comparable to gefitinib in inhibiting these cancer cell lines, and several of them even displayed superior inhibitory activity. In particular, analogue 5b with an IC50 of 0.10 μm against the EGFR wild-type A431 cells and 5c with an IC50 of 0.001 μm against the gefitinib-sensitive HCC827 cells (EGFR del E746-A750) was identified as highly active EGFR inhibitors. It was also significant that the discovered analogue 2f, not only has high potency against the gefitinib-sensitive cells (IC50 = 0.031 μm), but also possesses remarkably improved activity against the gefitinib-resistant cells. In addition, the enzymatic assays and the Western blot analysis for evaluating the effects of the typical inhibitors indicated that these molecules strongly interfere with the EGFR target.

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Design, Synthesis, and Biological Evaluation of Novel Conformationally Constrained Inhibitors Targeting Epidermal Growth Factor Receptor Threonine⁷⁹⁰ → Methionine⁷⁹⁰ Mutant

Cited by 79 publications

References 42 publications

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

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

Development of covalent inhibitors that can overcome resistance to first-generation FGFR kinase inhibitors

Novel Quinazoline Derivatives Bearing Various 4‐Aniline Moieties as Potent EGFR Inhibitors with Enhanced Activity Against NSCLC Cell Lines

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Design, Synthesis, and Biological Evaluation of Novel Conformationally Constrained Inhibitors Targeting Epidermal Growth Factor Receptor Threonine790 → Methionine790 Mutant

Cited by 79 publications

References 42 publications

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

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

Development of covalent inhibitors that can overcome resistance to first-generation FGFR kinase inhibitors

Novel Quinazoline Derivatives Bearing Various 4‐Aniline Moieties as Potent EGFR Inhibitors with Enhanced Activity Against NSCLC Cell Lines

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Product

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Design, Synthesis, and Biological Evaluation of Novel Conformationally Constrained Inhibitors Targeting Epidermal Growth Factor Receptor Threonine⁷⁹⁰ → Methionine⁷⁹⁰ Mutant