SH-1028, An Irreversible Third-Generation EGFR TKI, Overcomes T790M-Mediated Resistance in Non-Small Cell Lung Cancer
Open accessAbstract
SH-1028 is an irreversible third-generation EGFR TKI. Both SH-1028 and osimertinib have a pyrimidine structure (a typical mutant-selective EGFR TKI structure). Compared with osimertinib, SH-1028 is modified on the indole ring, thus resulting in a more stable 6,7,8,9-tetrahydro-pyrrolo [1, 2-a] indol structure. In this study, we explored the anti-tumor effect of SH-1028 in vitro and in vivo , the inhibition of cell signal, such as EGFR and ERK phosphorylation, and verified the relationship between the pharmacokinetics and pharmacodynamic responses. Firstly, SH-1028 selectively inhibited EGFR sensitive and resistant mutations, with up to 198-fold more effective compared with wild-type EGFR cells. Then, in mouse xenograft models, oral administration of SH-1028 at a daily dose of 5 mg/kg significantly inhibited proliferation of tumor cells with EGFR sensitive mutation (exon 19 del) and resistant mutation (T790 M) for consecutive 14 days, with no TKI-induced weight loss. Moreover, SH-1028 exhibited good bioavailability, and was distributed extensively from the plasma to the tissues. The main metabolite of SH-1028, Imp3, was tested and showed no wild-type EGFR inhibition or off-target effects. In conclusion, SH-1028 is a new third-generation EGFR inhibitor that exhibits potent activity against EGFR sensitive and resistant (T790 M) mutations.
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Oritinib overcomes T790M-mediated drug resistance in NSCLC and inhibits WT-EGFR, EGFRL858R, EGFRL861Q, EGFRL858R/T790M, EGFRd746-750, and EGFRd746-750/T790M kinases, with IC50 values of 18, 0.7, 4, 0.1, 1.4, and 0.89 nM, respectively.
“Oritinib overcomes T790M-mediated drug resistance in NSCLC and inhibits WT-EGFR, EGFRL858R, EGFRL861Q, EGFRL858R/T790M, EGFRd746-750, and EGFRd746-750/T790M kinases. IC50 were 18, 0.7, 4, 0.1, 1.4 and 0.89 nM, respectively.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [163]
Oritinib binds irreversibly to EGFR kinase by covalently bonding to Cys797 residues targeting ATP binding sites.
“Oritinib binds irreversibly to EGFR kinase by covalently bonding to form Cys797 residues targeting ATP binding sites.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [163]
Oritinib effectively and selectively targets mutated EGFR cell lines in vitro.
“Oritinib effectively and selectively targets mutated EGFR cell lines in vitro.142,163–165”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [163]
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Cites
Siegel, R. L., Miller, K. D., & Jemal, A. (2020) · CA: A Cancer Journal for Clinicians · doi:10.3322/caac.21590 · Cited by 20,444 · see citing works
Cancer statistics in China, 2015
Chen, W., Zheng, R., Baade, P. D., Zhang, S., Zeng, H., Bray, F., Jemal, A., Yu, X. Q., & He, J. (2016) · CA: A Cancer Journal for Clinicians · doi:10.3322/caac.21338 · Cited by 17,038 · see citing works
<i>EGFR</i> Mutations in Lung Cancer: Correlation with Clinical Response to Gefitinib Therapy
Paez, J. G., Jänne, P. A., Lee, J. C., Tracy, S., Greulich, H., Gabriel, S., Herman, P., Kaye, F. J., Lindeman, N., Boggon, T. J., et al. (2004) · Science · doi:10.1126/science.1099314 · Cited by 9,368 · see citing works
Osimertinib in Untreated <i>EGFR</i> -Mutated Advanced Non–Small-Cell Lung Cancer
Soria, J.-C., Ohe, Y., Vansteenkiste, J., Reungwetwattana, T., Chewaskulyong, B., Lee, K. H., Dechaphunkul, A., Imamura, F., Nogami, N., Kurata, T., et al. (2018) · New England Journal of Medicine · doi:10.1056/nejmoa1713137 · Cited by 5,508 · see citing works
<i>EGFR</i> 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 · see citing works
Osimertinib or Platinum–Pemetrexed in <i>EGFR</i> T790M–Positive Lung Cancer
Mok, T. S., Wu, Y.-L., Ahn, M.-J., Garassino, M. C., Kim, H. R., Ramalingam, S. S., Shepherd, F. A., He, Y., Akamatsu, H., Theelen, W. S. M. E., et al. (2017) · New England Journal of Medicine · doi:10.1056/nejmoa1612674 · Cited by 3,379 · see citing works
Overall Survival with Osimertinib in Untreated, <i>EGFR</i> -Mutated Advanced NSCLC
Ramalingam, S. S., Vansteenkiste, J., Planchard, D., Cho, B. C., Gray, J. E., Ohe, Y., Zhou, C., Reungwetwattana, T., Cheng, Y., Chewaskulyong, B., et al. (2020) · New England Journal of Medicine · doi:10.1056/nejmoa1913662 · Cited by 2,914 · see citing works
Yu, H. A., Arcila, M. E., Rekhtman, N., Sima, C. S., Zakowski, M. F., Pao, W., Kris, M. G., Miller, V. A., Ladanyi, M., & Riely, G. J. (2013) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-12-2246 · Cited by 2,454 · see citing works
Herbst, R. S., Heymach, J. V., & Lippman, S. M. (2008) · New England Journal of Medicine · doi:10.1056/nejmra0802714 · Cited by 2,388 · see citing works
Cross, D. A. E., Ashton, S. E., Ghiorghiu, S., Eberlein, C., Nebhan, C. A., Spitzler, P. J., Orme, J. P., Finlay, M. R. V., Ward, R. A., Mellor, M. J., et al. (2014) · Cancer Discovery · doi:10.1158/2159-8290.cd-14-0337 · Cited by 2,246 · see citing works
AZD9291 in EGFR Inhibitor–Resistant Non–Small-Cell Lung Cancer
Jänne, P. A., Yang, J. C.-H., Kim, D.-W., Planchard, D., Ohe, Y., Ramalingam, S. S., Ahn, M.-J., Kim, S.-W., Su, W.-C., Horn, L., et al. (2015) · New England Journal of Medicine · doi:10.1056/nejmoa1411817 · Cited by 2,116 · see citing works
Epidermal growth factor receptor (EGFR) signaling in cancer
Normanno, N., Luca, A. D., Bianco, C., Strizzi, L., Mancino, M., Maiello, M. R., Carotenuto, A., Feo, G. D., Caponigro, F., & Salomon, D. S. (2005) · Gene · doi:10.1016/j.gene.2005.10.018 · Cited by 2,035 · see citing works
Non-small cell lung cancer: current treatment and future advances
Zappa, C., & Mousa, S. A. (2016) · Translational Lung Cancer Research · doi:10.21037/tlcr.2016.06.07 · Cited by 1,944 · see citing works
Osimertinib in Resected EGFR -Mutated Non–Small-Cell Lung Cancer
Wu, Y.-L. L. C., Tsuboi, M., He, J., John, T., Grohé, C., Majem, M., Goldman, J. W., Лактионов, К. К., Kim, S., Kato, T., et al. (2020) · New England Journal of Medicine · doi:10.1056/nejmoa2027071 · Cited by 1,820 · see citing works
Fukuoka, M., Wu, Y.-L., Thongprasert, S., Sunpaweravong, P., Leong, S.-S., Sriuranpong, V., Chao, T.-Y., Nakagawa, K., Chu, D.-T., Saijo, N., et al. (2011) · Journal of Clinical Oncology · doi:10.1200/jco.2010.33.4235 · Cited by 1,581 · see citing works
Park, K., Tan, E.-H., O'Byrne, K., Zhang, L., Boyer, M., Mok, T., Hirsh, V., Yang, J. C.-H., Lee, K. H., Lu, S., et al. (2016) · The Lancet Oncology · doi:10.1016/s1470-2045(16)30033-x · Cited by 1,183 · see citing works
Gazdar, A. F. (2009) · Oncogene · doi:10.1038/onc.2009.198 · Cited by 991 · see citing works
Goss, G. D., Tsai, C., Shepherd, F. A., Bazhenova, L. A., Lee, J. S., Chang, G., Crinò, L., Satouchi, M., Chu, Q. S.-C., Hida, T., et al. (2016) · The Lancet Oncology · doi:10.1016/s1470-2045(16)30508-3 · Cited by 647 · see citing works
Wu, J.-Y., Yu, C.-J., Chang, Y.-C., Yang, C.-H., Shih, J.-Y., & Yang, P.-C. (2011) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-10-3408 · Cited by 463 · see citing works
Boire, A. A., Brastianos, P. K., Garzia, L., & Valiente, M. (2019) · Nature reviews. Cancer · doi:10.1038/s41568-019-0220-y · Cited by 455 · see citing works
Soria, J.-C., Felip, E., Cobo, M., Lu, S., Syrigos, K., Lee, K. H., Göker, E., Georgoulias, V., Li, W., Isla, D., et al. (2015) · The Lancet Oncology · doi:10.1016/s1470-2045(15)00006-6 · Cited by 433 · see citing works
Sun, Y., Ren, Y., Fang, Z., Li, C., Fang, R., Gao, B., Han, X., Tian, W., Pao, W. J., Chen, H., et al. (2010) · Journal of Clinical Oncology · doi:10.1200/jco.2010.29.6038 · Cited by 334 · see citing works
Epidemiology of lung cancer and lung cancer screening programs in China and the United States
Yang, D., Liu, Y., Bai, C., Wang, X., & Powell, C. A. (2019) · Cancer Letters · doi:10.1016/j.canlet.2019.10.009 · Cited by 325 · see citing works
Wu, Y.-L. L. C., Lee, J. S., Thongprasert, S., Yu, C., Zhang, L., Ladrera, G., Srimuninnimit, V., Sriuranpong, V., Sandoval-Tan, J., Zhu, Y., et al. (2013) · The Lancet Oncology · doi:10.1016/s1470-2045(13)70254-7 · Cited by 298 · see citing works
Lim, S. M., Syn, N. L. X., Cho, B. C., & Soo, R. A. (2018) · Cancer Treatment Reviews · doi:10.1016/j.ctrv.2018.02.006 · Cited by 289 · see citing works
Nagano, T., TACHIHARA, M. Y., & Nishimura, Y. (2018) · Cells · doi:10.3390/cells7110212 · Cited by 252 · see citing works
Yang, J. C.-H., Camidge, D. R., Yang, C.-T., Zhou, J., Guo, R., Chiu, C.-H., Chang, G.-C., Shiah, H.-S., Chen, Y., Wang, C.-C., et al. (2020) · Journal of Thoracic Oncology · doi:10.1016/j.jtho.2020.09.001 · Cited by 165 · see citing works
Self-citationLee, K. H. (2017) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2017.02.001 · Cited by 142 · see citing works
Ramalingam, S. S., Janne, P. A., Mok, T. S. K., O'Byrne, K. J., Boyer, M. J., von Pawel, J., Płużański, A., Shtivelband, M. I., Docampo, L. I., Bennouna, J., et al. (2014) · The Lancet Oncology · doi:10.1016/s1470-2045(14)70452-8 · Cited by 140 · see citing works
Dickinson, P. A., Cantarini, M., Collier, J., Frewer, P., Martin, S. W., Pickup, K., & Ballard, P. G. (2016) · Drug Metabolism and Disposition · doi:10.1124/dmd.115.069203 · Cited by 137 · see citing works
Shi, Y., Zhang, S., Hu, X., Feng, J., Ma, Z., Zhou, J., Yang, N., Wu, L., Liao, W., Zhong, D., et al. (2020) · Journal of Thoracic Oncology · doi:10.1016/j.jtho.2020.01.010 · Cited by 111 · see citing works
Self-citationRecent progress on third generation covalent EGFR inhibitors
Cheng, H., Nair, S. K., & Murray, B. W. (2016) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2016.02.067 · Cited by 110 · see citing works
EGFR as a Pharmacological Target in EGFR -Mutant Non-Small-Cell Lung Cancer: Where Do We Stand Now?
Ke, E., & Wu, Y.-L. L. C. (2016) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2016.09.003 · Cited by 99 · see citing works
Xu, X., Mao, L., Xu, W., Tang, W., Zhang, X., Xi, B., Xu, R., Fang, X., Liu, J., Fang, C., et al. (2016) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-16-0281 · Cited by 87 · see citing works
Self-citationEllis, P. M., Coakley, N., Feld, R. D., Kuruvilla, S., & Ung, Y. (2015) · Current Oncology · doi:10.3747/co.22.2566 · Cited by 69 · see citing works
Cheng, C., Wang, R., Li, Y., Pan, Y., Zhang, Y., Li, H., Zheng, D., Zheng, S., Shen, X., Sun, Y., et al. (2015) · Scientific Reports · doi:10.1038/srep13959 · Cited by 38 · see citing works
Absolute Bioavailability of Osimertinib in Healthy Adults
Vishwanathan, K., So, K., Thomas, K., Bramley, A., English, S., & Collier, J. (2018) · Clinical Pharmacology in Drug Development · doi:10.1002/cpdd.467 · Cited by 37 · see citing works
Edwards, R. L., Andan, C., Lalla, R. V., Lacouture, M. E., O’Brien, D., & Sequist, L. V. D. (2018) · Clinical journal of oncology nursing · doi:10.1188/18.cjon.542-548 · Cited by 22 · see citing works
Gurtner, K., Ebert, N., Pfitzmann, D., Eicheler, W., Zips, D., Baumann, M. A., & Krause, M. (2014) · Radiation Oncology · doi:10.1186/s13014-014-0261-z · Cited by 9 · see citing works
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Research works printed but not linked: 1
- Cao M. Chen W. (2019). Epidemiology of Lung Cancer in China. Thorac. Cancer 10 (1), 3– 7. 10.1111/1759-7714.12916 30485694 PMC6312841 · DOI
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Xie, X., Yu, T., Li, X., Zhang, N., Foster, L. J., Peng, C., Huang, W., & He, G. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01589-z · Cited by 396 · see citing works
Xiong, A., Ren, S., Liu, H., Miao, L., Wang, L., Chen, J., Li, W., Li, R., Wang, X., Lu, Z., et al. (2022) · Journal of Thoracic Oncology · doi:10.1016/j.jtho.2022.06.013 · Cited by 20 · see citing works
Self-citation
- Authors
- Han, L., Zhang, X., Wang, Z., Zhang, X., Zhao, L., Fu, W., Liang, X., Zhang, Z., & Wang, Y.
- Affiliations
- China Pharmaceutical University (CN)
- Nanjing Sanhome Pharmaceutical Co., Ltd. (China) (CN)
- Corresponding author
- Wang, Yong
- Venue
- Frontiers in Pharmacology
- Publisher
- Frontiers Media SA
- Published
- 2021-04-27
- Volume
- 12
- Pages
- 665253-665253
- ISSN
- 1663-9812 (ISSN-L)
- PMC
- PMC8111447
- OpenAlex
- W3157045546
- Cited by
- 31
- References
- 39
- Citations by year
- 2026: 6 · 2025: 7 · 2024: 5 · 2023: 7 · 2022: 5 · 2021: 1
- FWCI
- 2.92
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Frontiers in Pharmacology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Keywords
- third-generation EGFR tyrosine kinase inhibitors, T790M mutation, EGFR resistance, non-small cell lung cancer, osimertinib, ERK1/2 phosphorylation, pharmacokinetics, pharmacodynamics, exon 19 deletion, tumor xenografts, bioavailability
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