Start Selective and Rigidify: The Discovery Path toward a Next Generation of EGFR Tyrosine Kinase Inhibitors

Engelhardt, Harald; Böse, Dietrich; Petronczki, Mark; Scharn, Dirk; Bader, Gerd; Baum, Anke; Bergner, Andreas; Chong, Eugene; Döbel, Sandra; Egger, Georg; Engelhardt, Christian; Ettmayer, Peter; Fuchs, Julian E.; Gerstberger, Thomas; Gonnella, Nina C.; Grimm, Alexandra; Grondal, Elisabeth; Haddad, Nizar; Hopfgartner, Barbara; Kousek, Roland; Krawiec, Mariusz; Kriz, Monika; Lamarre, Lyne; Leung, Joyce C.; Mayer, Moriz; Patel, Nitinchandra D.; Simov, Biljana Peric; Reeves, Jonathan T.; Schnitzer, Renate; Schrenk, Andreas; Sharps, Bernadette; Solca, Flavio; Stadtmüller, Heinz; Tan, Zhulin; Wunberg, Tobias; Zoephel, Andreas; McConnell, Darryl B.

doi:10.1021/acs.jmedchem.9b01169

Cited by 97 publications

(99 citation statements)

References 62 publications

(121 reference statements)

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“…Thus, the compound profile of CH7233163, which selectively inhibit EGFR-Del19/T790M/C797S over EGFR WT and potent antitumor activity upon monotherapy, would benefit osimertinib-resistant patients. Recently, new ATP competitive EGFR TKIs, BI-4020 and its derivatives, were reported as mutant selective EGFR-Del19/T790M/C797S inhibitors (46). However, these compounds are reported as 10-fold weaker potency against L858R/T790M/C797S in biochemical assays.…”

Section: Discussionmentioning

confidence: 99%

CH7233163 Overcomes Osimertinib-Resistant EGFR-Del19/T790M/C797S Mutation

Kashima¹,

Kawauchi²,

Tanimura³

et al. 2020

Molecular Cancer Therapeutics

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Osimertinib is the only EGFR-tyrosine kinase inhibitor (TKI) capable of overcoming EGFR-T790M-mutated NSCLC, but osimertinib-resistant EGFR triple mutations (Del19/T790M/C797S or L858R/T790M/C797S) have been reported. Although allosteric EGFR TKIs (eg. EAI-045) which potentially overcome L858R/T790M/C797S have been identified, there are no effective inhibitors against Del19/T790M/C797S. In this study, we identified CH7233163 as having the potential to overcome EGFR-Del19/T790M/C797S. CH7233163 showed potent antitumor activities against tumor with EGFR-Del19/T790M/C797S in vitro and in vivo. In addition to EGFR-Del19/T790M/C797S, the characterization assays showed that CH7233163 more selectively inhibits various types of EGFR mutants (eg. L858R/T790M/C797S, L858R/T790M, Del19/T790M, Del19 and L858R) over wild-type (WT). Furthermore, crystal structure analysis suggested that CH7233163 is a non-covalent ATP competitive inhibitor for EGFR-Del19/T790M/C797S that utilizes multiple interactions with the EGFR's αC-helix-in conformation to achieve potent inhibitory activity and mutant selectivity. Therefore, we conclude that CH7233163 is a potentially effective therapy for osimertinib resistant patients, especially in cases of EGFR-Del19/T790M/C797S.

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Section: Discussionmentioning

confidence: 99%

CH7233163 Overcomes Osimertinib-Resistant EGFR-Del19/T790M/C797S Mutation

Kashima¹,

Kawauchi²,

Tanimura³

et al. 2020

Molecular Cancer Therapeutics

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“…The docking of M6 into the ATP pocket of EGFR L858R/T790M indicates that M6 adapted a binding mode similar to docetaxel as well as the co-crystal ligand; compound 1 had a docking energy score of −7.4 kcal/mol ( Figure 4 A). Compound 1 is a potent non-covalent inhibitor of EGFR del19 T790M C797S , with an IC 50 = 790 nM [ 34 ].…”

Section: Resultsmentioning

confidence: 99%

Synthesis, Anticancer Screening of Some Novel Trimethoxy Quinazolines and VEGFR2, EGFR Tyrosine Kinase Inhibitors Assay; Molecular Docking Studies

et al. 2021

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A new series of 8-methoxy-2-trimethoxyphenyl-3-substituted quinazoline-4(3)-one compounds were designed, synthesized, and screened for antitumor activity against three cell lines, namely, Hela, A549, and MDA compared to docetaxel as reference drug. The molecular docking was performed using Autodock Vina program and 20 ns molecular dynamics (MD) simulation was performed using GROMACS 2018.1 software. Compound 6 was the most potent antitumor of the new synthesized compounds and was evaluated as a VEGFR2 and EGFR inhibitor with (IC50, 98.1 and 106 nM respectively) compared to docetaxel (IC50, 89.3 and 56.1 nM respectively). Compounds 2, 6, 10, and 8 showed strong cytotoxic activities against the Hela cell line with IC50 of, 2.13, 2.8, 3.98, and 4.94 µM, respectively, relative to docetaxel (IC50, 9.65 µM). Compound 11 showed strong cytotoxic activity against A549 cell line (IC50, 4.03 µM) relative to docetaxel (IC50, 10.8 µM). Whereas compounds 6 and 9 showed strong cytotoxic activity against MDA cell line (IC50, 0.79, 3.42 µM, respectively) as compared to docetaxel (IC50, 3.98 µM).

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“…52 Most efforts have focused on development of reversible, ATP-competitive compounds that are effective against the T790M mutant. Examples include trisubstituted imidazoles (Figure 2f), [53][54][55] BI-4020 56 and brigatinib, 57 an inhibitor of the ALK kinase that also has activity against EGFR T790M. All of these compounds appear to make important interactions with conserved residues that are crucial for receptor function, such as K745, the catalytic lysine.…”

Section: Egfr-first-generation To Third-generation Inhibitors and Beyondmentioning

confidence: 99%

A structural perspective on targeting the RTK/Ras/MAP kinase pathway in cancer

Heppner

Eck

2021

Protein Science

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Precision oncology is premised on identifying and drugging proteins and pathways that drive tumorigenesis or are required for survival of tumor cells. Across diverse cancer types, the signaling pathway emanating from receptor tyrosine kinases on the cell surface to RAS and the MAP kinase pathway is the most frequent target of oncogenic mutations, and key proteins in this signaling axis including EGFR, SHP2, RAS, BRAF, and MEK have long been a focus in cancer drug discovery. In this review, we provide an overview of historical and recent efforts to develop inhibitors targeting these nodes with an emphasis on the role that an understanding of protein structure and regulation has played in inhibitor discovery and characterization. Beyond its well-established role in structure-based drug design, structural biology has revealed mechanisms of allosteric regulation, distinct effects of activating oncogenic mutations, and other vulnerabilities that have opened new avenues in precision cancer drug discovery.

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Start Selective and Rigidify: The Discovery Path toward a Next Generation of EGFR Tyrosine Kinase Inhibitors

Cited by 97 publications

References 62 publications

CH7233163 Overcomes Osimertinib-Resistant EGFR-Del19/T790M/C797S Mutation

CH7233163 Overcomes Osimertinib-Resistant EGFR-Del19/T790M/C797S Mutation

Synthesis, Anticancer Screening of Some Novel Trimethoxy Quinazolines and VEGFR2, EGFR Tyrosine Kinase Inhibitors Assay; Molecular Docking Studies

A structural perspective on targeting the RTK/Ras/MAP kinase pathway in cancer

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