The DOI matches its Crossref record; 30 of the 30 references it cites were found in a registry or an index.
Novel mutant-selective EGFR kinase inhibitors against EGFR T790M
Open accessAbstract
The clinical efficacy of epidermal growth factor receptor (EGFR) kinase inhibitors in EGFR-mutant non-small-cell lung cancer (NSCLC) is limited by the development of drug-resistance mutations, including the gatekeeper T790M mutation. Strategies targeting EGFR T790M with irreversible inhibitors have had limited success and are associated with toxicity due to concurrent inhibition of wild-type EGFR. All current EGFR inhibitors possess a structurally related quinazoline-based core scaffold and were identified as ATP-competitive inhibitors of wild-type EGFR. Here we identify a covalent pyrimidine EGFR inhibitor by screening an irreversible kinase inhibitor library specifically against EGFR T790M. These agents are 30- to 100-fold more potent against EGFR T790M, and up to 100-fold less potent against wild-type EGFR, than quinazoline-based EGFR inhibitors in vitro. They are also effective in murine models of lung cancer driven by EGFR T790M. Co-crystallization studies reveal a structural basis for the increased potency and mutant selectivity of these agents. These mutant-selective irreversible EGFR kinase inhibitors may be clinically more effective and better tolerated than quinazoline-based inhibitors. Our findings demonstrate that functional pharmacological screens against clinically important mutant kinases represent a powerful strategy to identify new classes of mutant-selective kinase inhibitors.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“In 2009, Pasi et al. identified a series of covalent pyrimidine EGFR inhibitors, including WZ 3146, WZ 4002, and WZ 8040, through screening a library of irreversible kinase inhibitors specific to EGFRT790M.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [203]
In the citing paper
“These agents are designed to specifically inhibit mutant EGFR (ie, 19del-EGFR, L858R-EGFR and/or T790M+EGFR), sparing the WT receptor.14–18”
From Mechanisms of resistance to EGFR-targeted drugs: lung cancer (2016) · cites this paper as [14]
In the citing paper
“The presence of the T790M mutation was observed in approximately 50% of the cases in which biopsy was obtained at the time of relapse following gefitinib or erlotinib treatment in patients with the exon 19 deletion or the L858R EGFR mutation.”
From Mechanisms of resistance to EGFR-targeted drugs: lung cancer (2016) · cites this paper as [14]
In the citing paper
“AZD9291 has a distinct chemical structure from the other third-generation TKIs, WZ4002 (34) and CO-1686 (35).”
From AZD9291, an Irreversible EGFR TKI, Overcomes T790M-Mediated Resistance to EGFR Inhibitors in Lung Cancer (2014) · cites this paper as [34]
In the citing paper
“C797 is located opposite T790 in the ATP binding pocket and forms a covalent bond with all third-generation TKIs and is necessary for the inhibitor to suppress EGFR (21).”
In the citing paper
“This approach has previously led to identification of clinically relevant drug resistance mutations to EGFR TKIs (30, 31).”
From Response Heterogeneity of EGFR and HER2 Exon 20 Insertions to Covalent EGFR and HER2 Inhibitors (2017) · cites this paper as [30]
In the citing paper
“Thus, the T790M structural alteration in essence “enabled” discovery of inhibitors that selectively inhibit T790M–bearing mutants, when in association with L858R or exon 19 deletions, relative to WT EGFR 58,59.”
From Structural, Biochemical, and Clinical Characterization of Epidermal Growth Factor Receptor (EGFR) Exon 20 Insertion Mutations in Lung Cancer (2013) · cites this paper as [58]
In the citing paper
“Examination of the crystal structure of WZ4002 in complex with EGFR T790M (14) reveals that both L718 and L844 are in direct contact with the inhibitor; L718 primarily with the aniline ring and L844 with the pyrimidine ring (Figure 2A).”
From EGFR Mutations and Resistance to Irreversible Pyrimidine-Based EGFR Inhibitors (2015) · cites this paper as [14]
In the citing paper
“Cysteine 797 is the site of covalent binding for all three of these agents (14–16).”
From EGFR Mutations and Resistance to Irreversible Pyrimidine-Based EGFR Inhibitors (2015) · cites this paper as [14]
In the citing paper
“They are not only more potent on EGFR T790M, but also selectively inhibit mutant over WT EGFR and hence should lead to increased clinical efficacy and less toxicity compared with afatinib (14–16).”
From EGFR Mutations and Resistance to Irreversible Pyrimidine-Based EGFR Inhibitors (2015) · cites this paper as [14]
In the citing paper
“C797 is the site of covalent binding of WZ4002 and previously demonstrated to lead to drug resistance if mutated to serine (14).”
From EGFR Mutations and Resistance to Irreversible Pyrimidine-Based EGFR Inhibitors (2015) · cites this paper as [14]
In the citing paper
“CO-1686 is structurally more closely related to WZ4002 than to AZD9291 and in all of the models tested CO-1686 is very similar in vitro to WZ4002 (14–16).”
From EGFR Mutations and Resistance to Irreversible Pyrimidine-Based EGFR Inhibitors (2015) · cites this paper as [14]
In the citing paper
“However, ENU mutagenesis studies have been predictive of clinical drug resistance mutations in several prior studies (14, 24).”
From EGFR Mutations and Resistance to Irreversible Pyrimidine-Based EGFR Inhibitors (2015) · cites this paper as [14]
In the citing paper
“In prior studies, introduction of C797S into the background of EGFR L858R/T790M or EGFR Del 19/T790M resulted in significant loss of cellular potency for WZ4002 (14).”
From EGFR Mutations and Resistance to Irreversible Pyrimidine-Based EGFR Inhibitors (2015) · cites this paper as [14]
In the citing paper
“Analogously, a non-covalent analogue of WZ4002, WZ4003, was ineffective in in vitro models of EGFR T790M (14).”
From EGFR Mutations and Resistance to Irreversible Pyrimidine-Based EGFR Inhibitors (2015) · cites this paper as [14]
In the citing paper
“These include the development of mutant selective EGFR kinase inhibitors, including WZ4002, CO-1686 and AZD9291, which to date have demonstrated encouraging efficacy in both preclinical models and in EGFR mutant NSCLC patients with EGFR T790M mediated drug resistance (14–18).”
From EGFR Mutations and Resistance to Irreversible Pyrimidine-Based EGFR Inhibitors (2015) · cites this paper as [14]
In the citing paper
“WZ4002 is a covalent pyrimidine EGFR inhibitor specifically designed against EGFR T790M that is 30–100 fold more potent against EGFR T790M, and up to 100 fold less potent against wild type EGFR than quinazoline based EGFR inhibitors in vitro and is effective in murine models of lung cancer driven by EGFR T790M [84].”
From A decade of EGFR inhibition in EGFR-mutated non small cell lung cancer (NSCLC): Old successes and future perspectives (2015) · cites this paper as [84]
In the citing paper
“Both 2G and 3G EGFR‐TKI are irreversible small‐molecule inhibitors that covalently bind to EGFR kinase by targeting the cysteine‐797 residue, located in the ATP binding pocket, and 3G EGFR‐TKI are considered to be more specific for EGFR sensitizing mutations than 2G EGFR‐TKI.12, 13, 14”
In the citing paper
“A third generation of EGFR inhibitors followed afatinib; these covalent inhibitors selectively target the T790M mutant over wild-type EGFR, and include WZ4002 (Dana–Farber Cancer Institute)43, osimertinib44,45 and rociletinib (Clovis Oncology; CO-1686)46 (Fig. 2c).”
From Advances in covalent drug discovery (2022) · cites this paper as [43]
In the citing paper
“Standard of care is rapidly changing with the development of third-generation, mutant-selective EGFR-TKIs that have activity against cells that harbor TKI-sensitive EGFR mutations. Unlike conventional EGFR-TKIs, this activity is maintained in the presence of T790M resistance mutation.8,9”
From Association Between Plasma Genotyping and Outcomes of Treatment With Osimertinib (AZD9291) in Advanced Non–Small-Cell Lung Cancer (2016) · cites this paper as [9]
In the citing paper
“Next-generation EGFR TKIs have since been developed specifically to target the T790M mutation, 17,18 and they have demonstrated high and durable responses in patients with advanced EGFRmutant NSCLC who have been previously treated and in whom firstor second-generation EGFR TKIs have failed.”
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Gefitinib or Carboplatin–Paclitaxel in Pulmonary Adenocarcinoma
Mok, T. S., Wu, Y.-L., Thongprasert, S., Yang, C.-H., Chu, D.-T., Saijo, N., Sunpaweravong, P., Han, B., Margono, B., Ichinose, Y., et al. (2009) · New England Journal of Medicine · doi:10.1056/nejmoa0810699 · Cited by 8,261
MET Amplification Leads to Gefitinib Resistance in Lung Cancer by Activating ERBB3 Signaling
Engelman, J. A., Zejnullahu, K., Mitsudomi, T., Song, Y., Hyland, C., Park, J. O., Lindeman, N., Gale, C.-M., Zhao, X., Christensen, J., et al. (2007) · Science · doi:10.1126/science.1141478 · Cited by 4,496
EGFR Mutation and Resistance of Non–Small-Cell Lung Cancer to Gefitinib
Kobayashi, S., Boggon, T. J., Dayaram, T., Jänne, P. A., Kocher, O., Meyerson, M., Johnson, B. E., Eck, M. J., Tenen, D. G., & Halmos, B. (2005) · New England Journal of Medicine · doi:10.1056/nejmoa044238 · Cited by 3,964
Self-citationPao, W., Miller, V. A., Politi, K. A., Riely, G. J., Somwar, R., Zakowski, M. F., Kris, M. G., & Varmus, H. (2005) · PLoS Medicine · doi:10.1371/journal.pmed.0020073 · Cited by 3,527
Screening for Epidermal Growth Factor Receptor Mutations in Lung Cancer
Rosell, R., Moran, T., Queralt, C., Porta, R., Cardenal, F., Camps, C., Majem, M., Lopez-Vivanco, G., Isla, D., Provencio, M., et al. (2009) · New England Journal of Medicine · doi:10.1056/nejmoa0904554 · Cited by 2,373
The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP
Yun, C.-H., Mengwasser, K. E., Toms, A. V., Woo, M. S., Greulich, H., Wong, K.-K., Meyerson, M., & Eck, M. J. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0709662105 · Cited by 2,118
Self-citationBIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models
Li, D., Ambrogio, L., Shimamura, T., Kubo, S., Takahashi, M., Chirieac, L. R., Padera, R. F., Shapiro, G. I., Baum, A., Himmelsbach, F., et al. (2008) · Oncogene · doi:10.1038/onc.2008.109 · Cited by 1,447
Self-citationDiscovery of a selective inhibitor of oncogenic B-Raf kinase with potent antimelanoma activity
Tsai, J., Lee, J. T., Wang, W., Zhang, J., Cho, H., Mamo, S., Bremer, R., Gillette, S., Kong, J., Haass, N. K., et al. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0711741105 · Cited by 1,346
Yun, C.-H., Boggon, T. J., Li, Y., Woo, M. S., Greulich, H., Meyerson, M., & Eck, M. J. (2007) · Cancer Cell · doi:10.1016/j.ccr.2006.12.017 · Cited by 1,192
Self-citationEngelman, J. A., Zejnullahu, K., Gale, C.-M., Lifshits, E., Gonzales, A. J., Shimamura, T., Zhao, F., Vincent, P. W., Naumov, G. N., Bradner, J. E., et al. (2007) · Cancer Research · doi:10.1158/0008-5472.can-07-1885 · Cited by 730
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Items 301–400 of 1,000
Barnes, T. A., O'Kane, G. M., Vincent, M. D., & Leighl, N. B. (2017) · Frontiers in Oncology · doi:10.3389/fonc.2017.00113 · Cited by 61
LY2874455 potently inhibits FGFR gatekeeper mutants and overcomes mutation-based resistance
Wu, D., Guo, M., Min, X., Dai, S., Li, M., Tan, S., Li, G., Chen, X., Ma, Y., Li, J., et al. (2018) · Chemical Communications · doi:10.1039/c8cc07546h · Cited by 61
Self-citationFerlenghi, F., Scalvini, L., Vacondio, F., Castelli, R., Bozza, N., Marseglia, G., Rivara, S., Lodola, A., Monica, S. L., Minari, R., et al. (2021) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2021.113786 · Cited by 63
Epidermal Growth Factor Receptor (EGFR) Signaling and Covalent EGFR Inhibition in Lung Cancer
Heuckmann, J. M., Rauh, D., & Thomas, R. K. (2012) · Journal of Clinical Oncology · doi:10.1200/jco.2012.43.1825 · Cited by 61
A Self-Priming Digital Polymerase Chain Reaction Chip for Multiplex Genetic Analysis
Yin, J., Zou, Z., Yin, F., Liang, H., Hu, Z., Fang, W., Lv, S., Zhang, T., Wang, B., & Mu, Y. (2020) · ACS Nano · doi:10.1021/acsnano.0c04177 · Cited by 60
Du, S., Hu, X., Menéndez‐Arias, L., Zhan, P., & Liu, X. (2024) · Drug Resistance Updates · doi:10.1016/j.drup.2024.101053 · Cited by 61
Irreversible Inhibition of Epidermal Growth Factor Receptor Activity by 3-Aminopropanamides
Carmi, C., Galvani, E., Vacondio, F., Rivara, S., Lodola, A., Russo, S., Aiello, S., Bordi, F., Costantino, G., Cavazzoni, A., et al. (2012) · Journal of Medicinal Chemistry · doi:10.1021/jm201507x · Cited by 60
Small-molecule EGFR tyrosine kinase inhibitors for the treatment of cancer
Lee, C., Shiao, H., Wang, W.-C., & Hsieh, H. (2014) · Expert Opinion on Investigational Drugs · doi:10.1517/13543784.2014.928283 · Cited by 60
Beauchamp, E. M., Woods, B. A., Dulak, A. M., Tan, L., Xu, C., Gray, N. S., Bass, A. J., Wong, K., Meyerson, M. M., & Hammerman, P. S. (2013) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-13-0817 · Cited by 60
Self-citationStructural and biochemical studies of the PDGFRA kinase domain
Liang, L., Yan, X.-E., Yin, Y., & Yun, C. (2016) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2016.06.117 · Cited by 60
Self-citationAllosteric inhibition of antiapoptotic MCL-1
Lee, S., Wales, T. E., Escudero, S., Cohen, D. T., Luccarelli, J., Gallagher, C. G., Cohen, N. A., Huhn, A. J., Bird, G. H., Engen, J. R., et al. (2016) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.3223 · Cited by 59
Self-citationYang, J., Wang, L., Liu, J., Zhong, L., Zheng, R., Xu, Y., Ji, P., Zhang, C., Wang, W., Lin, X., et al. (2012) · Journal of Medicinal Chemistry · doi:10.1021/jm301365e · Cited by 59
CXCR7 Reactivates ERK Signaling to Promote Resistance to EGFR Kinase Inhibitors in NSCLC
Becker, J. H., Gao, Y., Soucheray, M., Pulido, I., Kikuchi, E., Rodríguez, M. L., Gandhi, R., Lafuente-Sanchis, A., Aupí, M., Fernández-Coronado, J. A., et al. (2019) · Cancer Research · doi:10.1158/0008-5472.can-19-0024 · Cited by 59
Self-citationDemystifying Functional Parameters for Irreversible Enzyme Inhibitors
Heppner, D. E., Ogboo, B. C., Urul, D. A., May, E. W., Schaefer, E., Murkin, A. S., & Gehringer, M. (2024) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.4c01721 · Cited by 61
Zhang, X.-W., Li, L., Hu, W.-Q., Hu, M.-N., Tao, Y., Hu, H., Miao, X.-K., Yang, W.-L., Zhu, Q., & Mou, L. (2022) · Cell Death and Disease · doi:10.1038/s41419-021-04485-y · Cited by 59
Overcoming resistance to targeted therapies in NSCLC: current approaches and clinical application
Maione, P., Sacco, P. C., Sgambato, A., Casaluce, F., Rossi, A., & Gridelli, C. (2015) · Therapeutic Advances in Medical Oncology · doi:10.1177/1758834015595048 · Cited by 59
Grabinski, N., & Ewald, F. (2014) · Investigational New Drugs · doi:10.1007/s10637-014-0141-2 · Cited by 58
Hatcher, J. M., Zhang, J., Choi, H. G., Ito, G., Alessi, D. R., & Gray, N. S. (2015) · ACS Medicinal Chemistry Letters · doi:10.1021/acsmedchemlett.5b00064 · Cited by 58
Self-citationCalles, A., Kwiatkowski, N. P., Cammarata, B. K., Ercan, D., Gray, N. S., & Janne, P. A. (2014) · Molecular Oncology · doi:10.1016/j.molonc.2014.08.011 · Cited by 58
Self-citationCarfilzomib modulates tumor microenvironment to potentiate immune checkpoint therapy for cancer
Zhou, Q., Liang, J., Yang, T., Liu, J., Li, B., Li, Y., Fan, Z., Wang, W., Chen, W., Yuan, S., et al. (2021) · EMBO Molecular Medicine · doi:10.15252/emmm.202114502 · Cited by 57
Self-citationLaface, C., Maselli, F. M., Santoro, A. N., Iaia, M. L., Ambrogio, F., Laterza, M., Guarini, C., Santis, P. D., Perrone, M., & Fedele, P. (2023) · Pharmaceutics · doi:10.3390/pharmaceutics15061604 · Cited by 63
Impact of Genomics on Personalized Cancer Medicine
Arteaga, C. L., & Baselga, J. M. (2012) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-11-2019 · Cited by 57
Zhang, K., & Yuan, Q. (2016) · Journal of Cancer Research and Therapeutics · doi:10.4103/0973-1482.200613 · Cited by 57
Agajanian, S., Odeyemi, O., & Verkhivker, G. M. (2019) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2019.00044 · Cited by 57
Mechanisms of Resistance to EGFR Tyrosine Kinase Inhibitors and Therapeutic Approaches: An Update
Ahsan, A. (2015) · Advances in experimental medicine and biology · doi:10.1007/978-3-319-24223-1_7 · Cited by 56
Non-small-cell lung cancer harbouring mutations in the EGFR kinase domain
Rosell, R., Morán, T., Carcereny, E., Quiroga, V., Molina‐Vila, M. Á., Costa, C., Benlloch, S., & Tarón, M. (2010) · Clinical & Translational Oncology · doi:10.1007/s12094-010-0473-0 · Cited by 58
Qiu, Y., Yin, X., Li, X., Wang, Y., Fu, Q., Huang, R., & Lu, S. (2021) · Pharmaceutics · doi:10.3390/pharmaceutics13050747 · Cited by 55
Discovery of a Selective Irreversible BMX Inhibitor for Prostate Cancer
Liu, F., Zhang, X., Weisberg, E., Chen, S., Hur, W., Wu, H., Zhao, Z., Wang, W., Mao, M., Cai, C., et al. (2013) · ACS Chemical Biology · doi:10.1021/cb4000629 · Cited by 54
Self-citationSong, Z., Huang, S., Yu, H., Jiang, Y., Wang, C., Meng, Q., Shu, X. H., Sun, H., Liu, K., Li, Y., et al. (2017) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2017.03.083 · Cited by 54
Discovery of 2,4,6-trisubstitued pyrido[3,4-d]pyrimidine derivatives as new EGFR-TKIs
Zhang, H., Wang, J., Shen, Y. H., Wang, H., Duan, W.-M., Zhao, H., Hei, Y., Xin, M., Cao, Y., & Zhang, S. (2018) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2018.02.051 · Cited by 54
Bedi, S., Khan, S. A., AbuKhader, M., Alam, P., Siddiqui, N. A., & Husain, A. (2018) · Saudi Pharmaceutical Journal · doi:10.1016/j.jsps.2018.04.010 · Cited by 54
FDA-Approved Small Molecule Compounds as Drugs for Solid Cancers from Early 2011 to the End of 2021
Sochacka-Ćwikła, A., Mą̨czyński, M., & Regiec, A. (2022) · Molecules · doi:10.3390/molecules27072259 · Cited by 56
Sun, S., Wu, S.-H., Kang, J.-B., Ma, Y.-Y., Chen, L., Cao, P., Chang, L., Ding, N., Xue, X., Li, N., et al. (2022) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.2c00030 · Cited by 54
Self-citationCapoferri, L., Lodola, A., Rivara, S., & Mor, M. (2015) · Journal of Chemical Information and Modeling · doi:10.1021/ci500720e · Cited by 53
Jia, P., Jin, H., Meador, C. B., Xia, J., Ohashi, K., Liu, L., Pirazzoli, V., Dahlman, K. B., Politi, K. A., Michor, F., et al. (2013) · Genome Research · doi:10.1101/gr.152322.112 · Cited by 54
Tripathi, S. K., Pandey, K., Rengasamy, K. R. R., & Biswal, B. K. (2020) · Medicinal Research Reviews · doi:10.1002/med.21700 · Cited by 54
Discovery of a potent dual ALK and EGFR T790M inhibitor
Jang, J., Son, J. B., To, C., Bahcall, M., Kim, S. Y., Kang, S. Y., Mushajiang, M., Lee, Y., Janne, P. A., Choi, H. G., et al. (2017) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2017.04.079 · Cited by 51
Self-citationKatayama, S., Sueyoshi, N., Inazu, T., & Kameshita, I. (2020) · Neural Plasticity · doi:10.1155/2020/6970190 · Cited by 52
Wittlinger, F., Heppner, D. E., To, C., Günther, M., Shin, B. H., Rana, J. K., Schmoker, A. M., Beyett, T. S., Berger, L. M., Berger, B., et al. (2021) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.1c00848 · Cited by 51
Self-citationDiscovery of a BTK/MNK dual inhibitor for lymphoma and leukemia
Wu, H. Y., Hu, C., Wang, A., Weisberg, E., Chen, Y., Yun, C.-H., Wang, W., Liu, Y., Liu, X., Tian, B., et al. (2015) · Leukemia · doi:10.1038/leu.2015.180 · Cited by 52
Self-citationPerturbation of the mutated EGFR interactome identifies vulnerabilities and resistance mechanisms
Li, J., Bennett, K. L., Stukalov, A., Fang, B., Zhang, G., Yoshida, T., Okamoto, I., Kim, J., Song, L., Bai, Y., et al. (2013) · Molecular Systems Biology · doi:10.1038/msb.2013.61 · Cited by 51
Minkoff, B. B., Blatz, J. M., Choudhury, F. A., Benjamin, D., Shohet, J. L., & Sussman, M. R. (2017) · Scientific Reports · doi:10.1038/s41598-017-13371-7 · Cited by 51
Mancini, M., Gal, H., Gaborit, N., Mazzeo, L., Romaniello, D., Salame, T. M., Lindzen, M., Mahlknecht, G., Enuka, Y., Burton, D. G. A., et al. (2017) · EMBO Molecular Medicine · doi:10.15252/emmm.201708076 · Cited by 52
Basu, D., Richters, A., & Rauh, D. (2015) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2015.04.038 · Cited by 50
Sakuma, Y., Matsukuma, S., Nakamura, Y., Yoshihara, M., Koizume, S., Sekiguchi, H., Saito, H., Nakayama, H., Kameda, Y., Yokose, T., et al. (2013) · Laboratory Investigation · doi:10.1038/labinvest.2013.102 · Cited by 49
Kancha, R. K., Peschel, C., & Duyster, J. (2011) · Journal of Thoracic Oncology · doi:10.1097/jto.0b013e3182021f3e · Cited by 49
The relevance of tyrosine kinase inhibitors for global metabolic pathways in cancer
Turan, M. P., Aebersold, D. M., Zimmer, Y., & Medová, M. (2018) · Molecular Cancer · doi:10.1186/s12943-018-0798-9 · Cited by 50
Zhao, B., Xiao, Z., Qi, J., Luo, R., Zhou, L., Zhang, Y., Hu, X., Tang, Q., Zheng, P., Xu, S., et al. (2018) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2018.11.069 · Cited by 49
Epidermal growth factor receptor inhibitors in oncology
Vivanco, I., & Mellinghoff, I. K. (2010) · Current Opinion in Oncology · doi:10.1097/cco.0b013e32833edbdf · Cited by 48
Yu, L., Huang, M., Xu, T., Tong, L., Yan, X.-E., Zhang, Z., Xu, Y., Yun, C., Xie, H., Ding, K., et al. (2016) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2016.12.006 · Cited by 48
Self-citationTsakonas, G., Petris, L. D., & Ekman, S. (2017) · Cancer Treatment Reviews · doi:10.1016/j.ctrv.2017.02.004 · Cited by 48
Sakuma, Y. (2017) · Pathology International · doi:10.1111/pin.12553 · Cited by 48
Xu, J., Wang, J., & Zhang, S. (2017) · Oncotarget · doi:10.18632/oncotarget.21164 · Cited by 52
Sakuma, Y., Yamazaki, Y., Nakamura, Y., Yoshihara, M., Matsukuma, S., Nakayama, H., Yokose, T., Kameda, Y., Koizume, S., & Miyagi, Y. (2011) · Laboratory Investigation · doi:10.1038/labinvest.2011.187 · Cited by 48
Molecular Dynamics Analysis of Binding of Kinase Inhibitors to WT EGFR and the T790M Mutant
Park, J., McDonald, J. J., Petter, R. C., & Houk, K. N. (2016) · Journal of Chemical Theory and Computation · doi:10.1021/acs.jctc.5b01221 · Cited by 47
Ismail, M. A., Abusaif, M. S., El-Gaby, M. S. A., Ammar, Y. A., & Ragab, A. (2023) · RSC Advances · doi:10.1039/d3ra01635h · Cited by 47
Schneeberger, V. E., Ren, Y., Luetteke, N., Huang, Q., Chen, L., Lawrence, H. R., Lawrence, N. J., Haura, E. B., Koomen, J. M., Coppola, D., et al. (2015) · Oncotarget · doi:10.18632/oncotarget.3356 · Cited by 49
Self-citationWu, H. Y., Wang, A., Zhang, W., Wang, B., Chen, C., Wang, W., Chen, H., Ye, Z., Zhao, Z., Wang, L., et al. (2015) · Oncotarget · doi:10.18632/oncotarget.5182 · Cited by 48
Self-citationXu, N., Fang, W., Mu, L., Tang, Y., Gao, L., Ren, S., Cao, D., Zhou, L., Zhang, A., Liu, D., et al. (2015) · Oncotarget · doi:10.18632/oncotarget.6461 · Cited by 48
Self-citationDesign and synthesis of quinazolinones as EGFR inhibitors to overcome EGFR resistance obstacle
Patel, H., Pawara, R. H., Ansari, A., Noolvi, M. N., & Surana, S. J. (2017) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2017.03.039 · Cited by 47
Klüter, S., Simard, J. R., Rode, H. B., Grütter, C., Pawar, V. T., Raaijmakers, H. C. A., Barf, T. A., Rabiller, M., van Otterlo, W. A. L., & Rauh, D. (2010) · ChemBioChem · doi:10.1002/cbic.201000352 · Cited by 46
Inhibition of mutant EGFR in lung cancer cells triggers SOX2-FOXO6-dependent survival pathways
Rothenberg, S. M., Concannon, K., Cullen, S. J., Boulay, G., Turke, A. B., Faber, A. C., Lockerman, E. L., Rivera, M. N., Engelman, J. A., Maheswaran, S., et al. (2015) · eLife · doi:10.7554/elife.06132 · Cited by 49
Costa, D. B., & Kobayashi, S. S. (2015) · PubMed Central · doi:10.3978/j.issn.2218-6751.2015.05.05 · Cited by 46
Kinases inhibitors in lung cancer: From benchside to bedside
Singh, P. K., Singh, H., & Silakari, O. (2016) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2016.07.002 · Cited by 47
Ibrutinib targets mutant-EGFR kinase with a distinct binding conformation
Wang, A., Yan, X.-E., Wu, H. Y., Wang, W., Chen, H., Cheng, C., Zhao, Z., Zhao, P., Li, X., Wang, L., et al. (2016) · Oncotarget · doi:10.18632/oncotarget.11951 · Cited by 47
Self-citationNon-small cell lung cancer treatment (r)evolution: ten years of advances and more to come
Toschi, L., Rossi, S., Finocchiaro, G., & Santoro, A. (2017) · ecancermedicalscience · doi:10.3332/ecancer.2017.787 · Cited by 48
Current Strategies and Applications for Precision Drug Design
Wang, C., Xu, P., Zhang, L., Huang, J. L., Zhu, K., & Luo, C. (2018) · Frontiers in Pharmacology · doi:10.3389/fphar.2018.00787 · Cited by 47
Madic, J., Jovelet, C., Lopez, J., André, B., Fatien, J., Miran, I., Honoré, A., Mezquita, L., Besse, B., Lacroix, L., et al. (2018) · Oncotarget · doi:10.18632/oncotarget.26446 · Cited by 46
1,2,4-Oxadiazole derivatives targeting EGFR and c-Met degradation in TKI resistant NSCLC
Dokla, E. M. E., Fang, C., Abouzid, K. A. M., & Chen, C. (2019) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2019.111607 · Cited by 46
Liu, X., Xu-Liu, Pang, X., Yuan, X. Y., Yu, G.-X., Li, Y.-R., Guan, Y.-F., Zhang, Y., Song, J., Zhang, Q., et al. (2021) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2021.116358 · Cited by 46
Nanjo, S., Yamada, T., Nishihara, H., Takeuchi, S., Sano, T., Nakagawa, T., Ishikawa, D., Zhao, L., Ebi, H., Yasumoto, K., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0084700 · Cited by 45
Fong, J., Jacobs, R. J., Moravec, D. N., Uppada, S. B., Botting, G. M., Nlend, M., & Puri, N. (2013) · PLoS ONE · doi:10.1371/journal.pone.0078398 · Cited by 45
Frett, B., Carlomagno, F., Moccia, M. L., Brescia, A., Federico, G., Falco, V. D., Admire, B., Chen, Z., Qi, W., Santoro, M. M., et al. (2015) · Angewandte Chemie International Edition · doi:10.1002/anie.201501104 · Cited by 45
Epidermal Growth Factor Receptor–Mutant Lung Cancer
Piotrowska, Z., & Sequist, L. V. D. (2015) · The Cancer Journal · doi:10.1097/ppo.0000000000000147 · Cited by 45
Covalent EGFR Inhibitors: Binding Mechanisms, Synthetic Approaches, and Clinical Profiles
Hossam, M., Lasheen, D. S., & Abouzid, K. A. M. (2016) · Archiv der Pharmazie · doi:10.1002/ardp.201600063 · Cited by 45
Receptor Tyrosine Kinases: Structure, Functions and Role in Human Disease
Yarden, Y., & Wheeler, D. L. (2014) · Springer eBooks · doi:10.1007/978-1-4939-2053-2 · Cited by 44
Structural pharmacological studies on EGFR T790M/C797S
Kong, L., Ma, R., Yao, M.-Y., Yan, X.-E., Zhu, S., Zhao, P., & Yun, C. (2017) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2017.04.138 · Cited by 45
Self-citationIvanova, E. V., Kuraguchi, M., Xu, M., Portell, A. J., Taus, L. J., Diala, I., Lalani, A. S., Choi, J., Chambers, E. S., Li, S., et al. (2020) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-19-1844 · Cited by 45
Self-citationDesigning of kinase hinge binders: A medicinal chemistry perspective
Sharma, V., & Gupta, M. (2022) · Chemical Biology & Drug Design · doi:10.1111/cbdd.14024 · Cited by 44
Emerging Agents and New Mutations in EGFR-Mutant Lung Cancer
Ayeni, D. O., Politi, K. A., & Goldberg, S. B. (2015) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-15-1211 · Cited by 44
Mutational and network level mechanisms underlying resistance to anti-cancer kinase inhibitors
Mancini, M., & Yarden, Y. (2015) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2015.09.018 · Cited by 45
Kwak, E. L. (2011) · The Oncologist · doi:10.1634/theoncologist.2011-0087 · Cited by 44
Phan, A. N. H., Hua, T. N. M., Kim, M.-K., Vo, V. T. A., Choi, J.-W., Kim, H.-W., Rho, J. K., Kim, K. W., & Jeong, Y. (2016) · Oncotarget · doi:10.18632/oncotarget.10581 · Cited by 44
Ahmad, I., Shaikh, M., Surana, S. J., Ghosh, A., & Patel, H. (2020) · Journal of Biomolecular Structure and Dynamics · doi:10.1080/07391102.2020.1844801 · Cited by 44
Structural basis of mutant-selectivity and drug-resistance related to CO-1686
Yan, X.-E., Zhu, S.-J., Liang, L., Zhao, P., Choi, H. G., & Yun, C.-H. (2017) · Oncotarget · doi:10.18632/oncotarget.18588 · Cited by 43
Self-citationDong, H., Ye, X., Zhu, Y., Shen, H., Shen, H., Chen, W., Ji, M., Zheng, M., Wang, K., Cai, Z., et al. (2023) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.3c00277 · Cited by 43
Overcoming C797S mutation: The challenges and prospects of the fourth-generation EGFR-TKIs
Zhao, H., Xi, X.-X., Xin, M., & Zhang, S. (2022) · Bioorganic Chemistry · doi:10.1016/j.bioorg.2022.106057 · Cited by 43
Zhao, Z., Xie, L., Xie, L., & Bourne, P. E. (2016) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.5b02041 · Cited by 43
Liu, H., Qu, M., Xu, L., Han, X., Wang, C., Shu, X. H., Yao, J.-H., Liu, K., Peng, J., Li, Y., et al. (2017) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2017.04.037 · Cited by 42
Structural insights into drug development strategy targeting EGFR T790M/C797S
Zhu, S., Zhao, P., Yang, J., Ma, R., Yan, X.-E., Yang, S., Yang, J., & Yun, C. (2018) · Oncotarget · doi:10.18632/oncotarget.24113 · Cited by 42
Self-citationCarmi, C., Lodola, A., Rivara, S., Vacondio, F., Cavazzoni, A., Alfieri, R. R., Ardizzoni, A., Petronini, P. G., & Mor, M. (2011) · Mini-Reviews in Medicinal Chemistry · doi:10.2174/138955711797247725 · Cited by 42
Recent advances in JAK3 inhibition: Isoform selectivity by covalent cysteine targeting
Förster, M., Gehringer, M., & Laufer, S. (2017) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2017.07.079 · Cited by 42
Majem, M., & Remón, J. (2013) · Europe PMC (PubMed Central) · doi:10.3978/j.issn.2218-6751.2013.03.09 · Cited by 41
Sacher, A. G., Janne, P. A., & Oxnard, G. R. (2014) · Cancer · doi:10.1002/cncr.28723 · Cited by 42
Patel, H., Shaikh, M., Ahmad, I., Lokwani, D. K., & Surana, S. J. (2020) · Journal of Biomolecular Structure and Dynamics · doi:10.1080/07391102.2020.1754918 · Cited by 41
EGFR-Targeted Therapies: A Literature Review
Sha, C., & Lee, P. C. (2024) · Journal of Clinical Medicine · doi:10.3390/jcm13216391 · Cited by 43
Ai, X., Sun, Y., Wang, H., & Lü, S. (2014) · Amino Acids · doi:10.1007/s00726-014-1716-0 · Cited by 40
Blakely, C. M., & Bivona, T. G. (2012) · Cancer Discovery · doi:10.1158/2159-8290.cd-12-0387 · Cited by 39
Chemical Interrogation of the Malaria Kinome
Derbyshire, E. R., Zuzarte‐Luís, V., Magalhães, A. D., Kato, N., Sanschagrin, P. C., Wang, J., Zhou, W., Miduturu, C. V., Mazitschek, R., Piotr Sliz, A., et al. (2014) · ChemBioChem · doi:10.1002/cbic.201400025 · Cited by 39
Self-citationRicciuti, B., Baglivo, S., Paglialunga, L., Giglio, A. D., Bellezza, G., Chiari, R., Crinò, L., & Metro, G. (2017) · Therapeutic Advances in Medical Oncology · doi:10.1177/1758834017702820 · Cited by 39
Metadata
- Authors
- Zhou, W., Ercan, D., Chen, L., Yun, C.-H., Li, D., Capelletti, M., Cortot, A. B., Chirieac, L., Iacob, R. E., Padera, R., Engen, J. R., Wong, K.-K., Eck, M. J., Gray, N. S., & Jänne, P. A.
- Affiliations
- Dana-Farber Cancer Institute (US)
- Brigham and Women's Hospital (US)
- Northeastern University (US)
- Corresponding author
- Gray, Nathanael S.
- ORCID
- Venue
- Nature
- Published
- 2009-12
- Volume
- 462
- Issue
- 7276
- Pages
- 1070-1074
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC2879581
- OpenAlex
- W2133963438
- Cited by
- 1,013
- References
- 30
- Citations by year
- 2026: 32 · 2025: 43 · 2024: 39 · 2023: 60 · 2022: 46 · 2021: 55 · 2020: 62 · 2019: 55 · 2018: 66 · 2017: 84 · 2016: 82 · 2015: 75 · 2014: 71 · 2013: 82 · 2012: 54
- FWCI
- 45.89
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institute on Aging (R01AG2400401)
- National Cancer Institute (R01CA116020, R01CA122794, R01CA130876, R01CA11446, P50CA090578, R01CA135257, R01CA080942)
- National Institute of General Medical Sciences (R01GM070590)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- EGFR kinase inhibitors, mutant-selective inhibitors, irreversible kinase inhibitors, non-small cell lung cancer, drug resistance, co-crystallization, gatekeeper mutation
- MeSH terms
- Animals, Antineoplastic Agents, Drug Evaluation, Preclinical, Lung, Models, Chemical, Models, Molecular, Mutation, Phosphorylation, Drug Resistance, Neoplasm, NIH 3T3 Cells, Cell Line, Tumor, Protein Kinase Inhibitors, Cell Proliferation, Mice, ErbB Receptors
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
