Insight into the Inhibition of Drug‐Resistant Mutants of the Receptor Tyrosine Kinase EGFR

Engel, Julian; Becker, Christian; Lategahn, Jonas; Keul, Marina; Ketzer, Julia; Mühlenberg, Thomas; Kollipara, Laxmikanth; Schultz‐Fademrecht, Carsten; Zahedi, René P.; Bauer, Sebastian; Rauh, Daniel

doi:10.1002/anie.201605011

Cited by 56 publications

(62 citation statements)

References 24 publications

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“…We designed CRIs based on the crystal structures of covalent pyrazolo[3,2- d ]pyrimidines (PDB: 5j9y), which showed excellent inhibition of drug-resistant EGFR T790M both in biochemical and cellular assays ( Figure 1 ). 46 We chose to focus on bulky aromatic ring systems as substituents at the 3-position to extend the inhibitor into the lipophilic pocket adjacent to the gatekeeper residue (Met790) and to achieve mutant selectivity by favorable interactions. To render the inhibitor covalent-reversible, we modified the attached Michael acceptor by inserting an electron-withdrawing group.…”

Section: Resultsmentioning

confidence: 99%

“…We could show that these inhibitors showed excellent inhibitory effects against drug-resistant EGFR L858R/T790M cell lines, as well as demonstrating a highly promising selectivity toward the drug-resistant variants and a favorable kinetic profile. 46 We combined these findings with lessons learned from Basu et al, wherein we developed CRIs based upon the third-generation EGFR L858R/T790M inhibitor, WZ 4002. 38 Herein, we were able to show that a small library of CRIs inhibited the drug-resistant variants of EGFR better than their reversible analogs.…”

Section: Introductionmentioning

confidence: 99%

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Characterization of Covalent-Reversible EGFR Inhibitors

et al. 2017

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Within the spectrum of kinase inhibitors, covalent-reversible inhibitors (CRIs) provide a valuable alternative approach to classical covalent inhibitors. This special class of inhibitors can be optimized for an extended drug-target residence time. For CRIs, it was shown that the fast addition of thiols to electron-deficient olefins leads to a covalent bond that can break reversibly under proteolytic conditions. Research groups are just beginning to include CRIs in their arsenal of compound classes, and, with that, the understanding of this interesting set of chemical warheads is growing. However, systems to assess both characteristics of the covalent-reversible bond in a simple experimental setting are sparse. Here, we have developed an efficient methodology to characterize the covalent and reversible properties of CRIs and to investigate their potential in targeting clinically relevant variants of the receptor tyrosine kinase EGFR.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Characterization of Covalent-Reversible EGFR Inhibitors

et al. 2017

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“…In the clinical setting, a subset of NSCLC patients respond well to small-molecule inhibitors of the EGF receptor, such as Erlotinib (Tarceva, Roche) 32 . Unfortunately, therapy resistance is a frequent occurrence despite initial treatment success, leading to disease relapse 33 , 34 . Given the ability of 8 to induce apoptosis in HCC-827 cells, we asked whether it could also induce apoptosis in HCC-827-derived Erlotinib-resistant cells.…”

Section: Resultsmentioning

confidence: 99%

Development of Erasin: a chromone-based STAT3 inhibitor which induces apoptosis in Erlotinib-resistant lung cancer cells

Lis

Rubner

Roatsch

et al. 2017

Sci Rep

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Inhibition of protein-protein interactions by small molecules offers tremendous opportunities for basic research and drug development. One of the fundamental challenges of this research field is the broad lack of available lead structures from nature. Here, we demonstrate that modifications of a chromone-based inhibitor of the Src homology 2 (SH2) domain of the transcription factor STAT5 confer inhibitory activity against STAT3. The binding mode of the most potent STAT3 inhibitor Erasin was analyzed by the investigation of structure-activity relationships, which was facilitated by chemical synthesis and biochemical activity analysis, in combination with molecular docking studies. Erasin inhibits tyrosine phosphorylation of STAT3 with selectivity over STAT5 and STAT1 in cell-based assays, and increases the apoptotic rate of cultured NSCLC cells in a STAT3-dependent manner. This ability of Erasin also extends to HCC-827 cells with acquired resistance against Erlotinib, a clinically used inhibitor of the EGF receptor. Our work validates chromone-based acylhydrazones as privileged structures for antagonizing STAT SH2 domains, and demonstrates that apoptosis can be induced in NSCLC cells with acquired Erlotinib resistance by direct inhibition of STAT3.

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“…Recently, the Bruton tyrosine kinase (BTK) inhibitor 4‐amino pyrazolopyrimidine scaffold has been developed as a new class of covalent mutant‐selective EGFR T790M inhibitors (Figure ) . The compounds exhibited high activity against EGFR L858R and EGFR L858R/T790M with good selectivity over EGFR WT .…”

Section: Fourth‐generation Inhibitors Overcoming Egfrc797smentioning

confidence: 99%

Targeting EGFR^L858R/T790M and EGFR^{L858R/T790M/C797S} resistance mutations in NSCLC: Current developments in medicinal chemistry

Zhang

et al. 2018

Medicinal Research Reviews

125

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Both the first-generation reversible epidermal growth factor receptor (EGFR) inhibitors gefitinib and erlotinib and the second-generation covalent epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) afatinib have significantly improved the survival of non-small-cell lung cancer (NSCLC) patients with activating EGFR mutations. However, a secondary EGFR mutation leads to the clinically acquired resistance to the first- and second-generation EGFR-TKIs drugs. A number of the third-generation wild-type sparing EGFR inhibitors, for example, WZ4002, CO1686, AZD9291, HM61713, EGF816, ASP8173, and PF0674775, have been developed, among which AZD9291 has been approved by US FDA for the treatment of NSCLC patients with EGFR . More recently, a tertiary EGFR mutation was reported as the dominant resistance mechanism to the third-generation irreversible inhibitors. It is highly desirable to develop the fourth-generation EGFR inhibitors. This review summarizes the mechanisms of acquired resistance and the latest medicinal chemistry advances on the third- and fourth-generation EGFR inhibitors, with special attention being paid to the allosteric and reversible inhibitors combating the tertiary EGFR mutation.

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Insight into the Inhibition of Drug‐Resistant Mutants of the Receptor Tyrosine Kinase EGFR

Cited by 56 publications

References 24 publications

Characterization of Covalent-Reversible EGFR Inhibitors

Characterization of Covalent-Reversible EGFR Inhibitors

Development of Erasin: a chromone-based STAT3 inhibitor which induces apoptosis in Erlotinib-resistant lung cancer cells

Targeting EGFR^L858R/T790M and EGFR^{L858R/T790M/C797S} resistance mutations in NSCLC: Current developments in medicinal chemistry

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Insight into the Inhibition of Drug‐Resistant Mutants of the Receptor Tyrosine Kinase EGFR

Cited by 56 publications

References 24 publications

Characterization of Covalent-Reversible EGFR Inhibitors

Characterization of Covalent-Reversible EGFR Inhibitors

Development of Erasin: a chromone-based STAT3 inhibitor which induces apoptosis in Erlotinib-resistant lung cancer cells

Targeting EGFRL858R/T790M and EGFRL858R/T790M/C797S resistance mutations in NSCLC: Current developments in medicinal chemistry

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Targeting EGFR^L858R/T790M and EGFR^{L858R/T790M/C797S} resistance mutations in NSCLC: Current developments in medicinal chemistry