AI Article Synopsis
- EGFR inhibitors effectively treat non-small cell lung cancer (NSCLC), but many patients develop resistance, mainly due to the T790M mutation, often alongside L858R.
- Resistance to these treatments leads to disease progression, and EGFR wild type inhibition can cause significant side effects like rash and diarrhea.
- A new compound, lead 12, has been identified as a selective irreversible inhibitor that targets the T790M and L858R mutations without affecting the wild type EGFR, showing promising tumor growth inhibition in preclinical studies.
Article Abstract
Epidermal growth factor receptor (EGFR) inhibitors have clinical utility in the treatment of non-small cell lung cancer (NSCLC) patients. Despite encouraging clinical efficacy with these agents, many patients develop resistance due to sensitizing (or activating) mutations ultimately leading to disease progression. In the majority of the cases, this resistance is due to the T790M mutation and frequently coexisting L858R. In addition, EGFR wild type receptor inhibition can lead to on target related dose limiting toxicities such as rash and diarrhea. We describe herein the identification of a mutant selective lead compound 12, an irreversible covalent inhibitor of EGFR T790M/L858R resistance mutations with selectivity over the wild type form. Significant tumor growth inhibition in preclinical models was observed with this lead.
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| http://dx.doi.org/10.1016/j.bmcl.2021.128406 | DOI Listing |
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