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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]
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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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