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A Chemical Tuned Strategy to Develop Novel Irreversible EGFR-TK Inhibitors with Improved Safety and Pharmacokinetic Profiles
- Source :
- Journal of Medicinal Chemistry. 57:9889-9900
- Publication Year :
- 2014
- Publisher :
- American Chemical Society (ACS), 2014.
-
Abstract
- Gatekeeper T790 M mutation in EGFR is the most prevalent factor underlying acquired resistance. Acrylamide-bearing quinazoline derivatives are powerful irreversible inhibitors for overcoming resistance. Nevertheless, concerns about the risk of nonspecific covalent modification have motivated the development of novel cysteine-targeting inhibitors. In this paper, we demonstrate that fluoro-substituted olefins can be tuned to alter Michael addition reactivity. Incorporation of these olefins into the quinazoline templates produced potent EGFR inhibitors with improved safety and pharmacokinetic properties. A lead compound 5a was validated against EGFR(WT), EGFR(T790M) as well as A431 and H1975 cancer cell lines. Additionally, compound 5a displayed a weaker inhibition against the EGFR-independent cancer cell line SW620 when compared with afatinib. Oral administration of 5a at a dose of 30 mg/kg induced tumor regression in a murine-EGFR(L858R/T790M) driven H1975 xenograft model. Also, 5a exhibited improved oral bioavailability and safety as well as favorable tissue distribution properties and enhanced brain uptake. These findings provide the basis of a promising strategy toward the treatment of NSCLC patients with drug resistance.
- Subjects :
- Lung Neoplasms
Afatinib
Antineoplastic Agents
Drug resistance
Pharmacology
chemistry.chemical_compound
T790M
Pharmacokinetics
Cell Line, Tumor
Drug Discovery
Quinazoline
medicine
Animals
Humans
Protein Kinase Inhibitors
EGFR inhibitors
Mice, Inbred BALB C
Xenograft Model Antitumor Assays
Ether-A-Go-Go Potassium Channels
Bioavailability
ErbB Receptors
chemistry
Drug Resistance, Neoplasm
Molecular Medicine
Lead compound
medicine.drug
Subjects
Details
- ISSN :
- 15204804 and 00222623
- Volume :
- 57
- Database :
- OpenAIRE
- Journal :
- Journal of Medicinal Chemistry
- Accession number :
- edsair.doi.dedup.....2d0e8e870b4d4d3fc378599b730dbd7c