Oxopyrido[2,3-d]pyrimidines as Covalent L858R/T790M Mutant Selective Epidermal Growth Factor Receptor (EGFR)
Ryan P Wurz1, Liping H Pettus1, Kate Ashton1
1Medicinal Chemistry, Oncology Research, Molecular Structure, Pharmacokinetics and Drug Metabolism, Oral Delivery - Product and Process Development, Discovery Toxicology, Pathology, Chemical Process R&D, Amgen Inc. , One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States.
Abstract:
In nonsmall cell lung cancer (NSCLC), the threonine(790)-methionine(790) (T790M) point mutation of EGFR kinase is one of the leading causes of acquired resistance to the first generation tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib. Herein, we describe the optimization of a series of 7-oxopyrido[2,3-d]pyrimidinyl-derived irreversible inhibitors of EGFR kinase. This led to the discovery of compound 24 which potently inhibits gefitinib-resistant EGFR(L858R,T790M) with 100-fold selectivity over wild-type EGFR. Compound 24 displays strong antiproliferative activity against the H1975 nonsmall cell lung cancer cell line, the first line mutant HCC827 cell line, and promising antitumor activity in an EGFR(L858R,T790M) driven H1975 xenograft model sparing the side effects associated with the inhibition of wild-type EGFR.
Insights
A new drug, compound 24, effectively targets resistant EGFR mutations in nonsmall cell lung cancer (NSCLC). It shows strong anticancer activity in cell lines and models, with reduced side effects compared to older treatments.
Area of Science:
- Medicinal Chemistry
- Oncology
- Molecular Biology
Background:
- Epidermal growth factor receptor (EGFR) mutations drive nonsmall cell lung cancer (NSCLC).
- The T790M mutation confers resistance to first-generation EGFR tyrosine kinase inhibitors (TKIs).
- Acquired resistance to TKIs remains a significant challenge in NSCLC treatment.
Purpose of the Study:
- To develop novel irreversible EGFR kinase inhibitors.
- To identify potent inhibitors targeting EGFR mutations, including T790M.
- To discover compounds with improved selectivity for mutant EGFR over wild-type EGFR.
Main Methods:
- Optimization of 7-oxopyrido[2,3-d]pyrimidine derivatives.
- In vitro kinase inhibition assays for EGFR(L858R,T790M) and wild-type EGFR.
- Antiproliferative assays using NSCLC cell lines (H1975, HCC827).
- In vivo efficacy studies in an EGFR(L858R,T790M) xenograft mouse model.
Main Results:
- Discovery of compound 24, a potent inhibitor of gefitinib-resistant EGFR(L858R,T790M).
- Compound 24 demonstrated 100-fold selectivity for mutant EGFR over wild-type EGFR.
- Significant antiproliferative activity observed in H1975 and HCC827 cell lines.
- Promising antitumor activity in a xenograft model with minimal side effects.
Conclusions:
- Compound 24 represents a promising therapeutic candidate for T790M-mutant NSCLC.
- Selective inhibition of mutant EGFR may mitigate side effects associated with wild-type EGFR inhibition.
- Further clinical investigation of compound 24 is warranted for NSCLC treatment.
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