The DOI matches its Crossref record; 44 of the 44 references it cites were found in a registry or an index.
Discovery of N-((3 R,4 R)-4-Fluoro-1-(6-((3-methoxy-1-methyl-1 H-pyrazol-4-yl)amino)-9-methyl-9 H-purin-2-yl)pyrrolidine-3-yl)acrylamide (PF-06747775) through Structure-Based Drug Design: A High Affinity Irreversible Inhibitor Targeting Oncogenic EGFR Mutants with Selectivity over Wild-Type EGFR
Abstract
Mutant epidermal growth factor receptor (EGFR) is a major driver of non-small-cell lung cancer (NSCLC). Marketed first generation inhibitors, such as erlotinib, effect a transient beneficial response in EGFR mutant NSCLC patients before resistance mechanisms render these inhibitors ineffective. Secondary oncogenic EGFR mutations account for approximately 50% of relapses, the most common being the gatekeeper T790M substitution that renders existing therapies ineffective. The discovery of PF-06459988 (1), an irreversible pyrrolopyrimidine inhibitor of EGFR T790M mutants, was recently disclosed.1 Herein, we describe our continued efforts to achieve potency across EGFR oncogenic mutations and improved kinome selectivity, resulting in the discovery of clinical candidate PF-06747775 (21), which provides potent EGFR activity against the four common mutants (exon 19 deletion (Del), L858R, and double mutants T790M/L858R and T790M/Del), selectivity over wild-type EGFR, and desirable ADME properties. Compound 21 is currently being evaluated in phase-I clinical trials of mutant EGFR driven NSCLC.
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“Mavelertinib (PF-06747775) (67) is an orally available and irreversible EGFR TKI that selectively targets various EGFR mutants, such as Del, L858R, T790M/L858R and T790M/Del, with less than 50% effect or inhibition against all nonkinase targets.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [196]
Citations
Cites
Understanding organofluorine chemistry. An introduction to the C–F bond
O’Hagan, D. (2007) · Chemical Society Reviews · doi:10.1039/b711844a · Cited by 4,128
Epidermal growth factor receptor mutations in lung cancer
Sharma, S. V., Bell, D. W., Settleman, J., & Haber, D. A. (2007) · Nature Reviews Cancer · doi:10.1038/nrc2088 · Cited by 3,170
The resurgence of covalent drugs
Singh, J., Petter, R. C., Baillie, T. A., & Whitty, A. (2011) · Nature Reviews Drug Discovery · doi:10.1038/nrd3410 · Cited by 1,873
A Medicinal Chemist’s Guide to Molecular Interactions
Bissantz, C., Kuhn, B., & Ståhl, M. (2010) · Journal of Medicinal Chemistry · doi:10.1021/jm100112j · Cited by 1,810
Novel mutant-selective EGFR kinase inhibitors against EGFR T790M
Zhou, W., Ercan, D., Chen, L., Yun, C.-H., Li, D., Capelletti, M., Cortot, A. B., Chirieac, L., Iacob, R. E., Padera, R., et al. (2009) · Nature · doi:10.1038/nature08622 · Cited by 1,013
Engelman, 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
Understanding resistance to EGFR inhibitors—impact on future treatment strategies
Wheeler, D. L., Dunn, E. F., & Harari, P. M. (2010) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2010.97 · Cited by 683
Finlay, M. R. V., Anderton, M., Ashton, S., Ballard, P., Bethel, P. A., Box, M. R., Bradbury, R. H., Brown, S. J., Butterworth, S., Campbell, A., et al. (2014) · Journal of Medicinal Chemistry · doi:10.1021/jm500973a · Cited by 636
Concise review of the glutathione S-transferases and their significance to toxicology
Eaton, D. L. (1999) · Toxicological Sciences · doi:10.1093/toxsci/49.2.156 · Cited by 627
Johnson, T. W., Richardson, P., Bailey, S., Brooun, A., Burke, B. J., Collins, M. R., Cui, J. J., Deal, J. G., Deng, Y., Dinh, D. M., et al. (2014) · Journal of Medicinal Chemistry · doi:10.1021/jm500261q · Cited by 621
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- 10.1073/pnas.1313733111 · DOI · Paper page
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Wu, S., & Shih, J. (2018) · Molecular Cancer · doi:10.1186/s12943-018-0777-1 · Cited by 802
Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials
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
Lipophilic Efficiency as an Important Metric in Drug Design
Johnson, T. W., Gallego, R. A., & Edwards, M. P. (2018) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.8b00077 · Cited by 385
Self-citationAyati, A., Moghimi, S., Salarinejad, S., Safavi, M., Pouramiri, B., & Foroumadi, A. (2020) · Bioorganic Chemistry · doi:10.1016/j.bioorg.2020.103811 · Cited by 394
Third generation EGFR TKIs: current data and future directions
Tan, C., Kumarakulasinghe, N. B., Huang, Y., Ang, Y. L. E., Choo, J. R.-E., Goh, B.-C., & Soo, R. A. (2018) · Molecular Cancer · doi:10.1186/s12943-018-0778-0 · Cited by 322
Metadata
- Authors
- Planken, S., Behenna, D. C., Nair, S. K., Johnson, T. O., Nagata, A., Almaden, C., Bailey, S., Ballard, T. E., Bernier, L., Cheng, H., Cho-Schultz, S., Dalvie, D., Deal, J. G., Dinh, D. M., Edwards, M. P., Ferre, R. A., Gajiwala, K. S., Hemkens, M., Kania, R. S., Kath, J. C., Matthews, J., Murray, B. W., Niessen, S., Orr, S. T. M., Pairish, M., Sach, N. W., Shen, H., Shi, M., Solowiej, J., Tran, K., Tseng, E., Vicini, P., Wang, Y., Weinrich, S. L., Zhou, R., Zientek, M., Liu, L., Luo, Y., Xin, S., Zhang, C., & Lafontaine, J.
- Affiliations
- Pfizer (United States) (US)
- WuXi AppTec (China) (CN)
- Corresponding author
- Planken, Simon
- Behenna, Douglas C.
- ORCID
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2017-03-29
- Volume
- 60
- Issue
- 7
- Pages
- 3002-3019
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- OpenAlex
- W2597231917
- Cited by
- 97
- References
- 44
- Citations by year
- 2026: 8 · 2025: 12 · 2024: 12 · 2023: 5 · 2022: 10 · 2021: 10 · 2020: 12 · 2019: 9 · 2018: 10 · 2017: 9
- FWCI
- 10.40
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Medicinal Chemistry (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Drug Discovery › Computational Drug Discovery Methods
- Physical Sciences › Chemistry › Organic Chemistry › Heterocyclic Compound Synthesis and Bioactivity
- Keywords
- EGFR inhibitors, T790M mutation, non-small cell lung cancer, irreversible kinase inhibitors, structure-based drug design, pyrrolopyrimidine, exon 19 deletion, L858R mutation, gatekeeper mutation, kinase selectivity, ADME properties, erlotinib resistance
- MeSH terms
- Acrylamides, Animals, Carcinoma, Non-Small-Cell Lung, Dogs, Humans, Lung, Lung Neoplasms, Models, Molecular, Mutation, Pyrrolidines, Drug Design, Cell Line, Tumor, Protein Kinase Inhibitors, Mice, Rats, Halogenation, Molecular Docking Simulation, ErbB Receptors
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