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Deciphering the Structural Effects of Activating EGFR Somatic Mutations with Molecular Dynamics Simulation
Published on: May 20, 2020
Structure optimization and discovery of novel compound for the treatment of insertion mutations within exon 20 of
Yetong Cui1, Ruonan Wang1, Yujiao Wei1
1The State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Nankai University, Tianjin 300071, PR China.
Abstract:
In previous decades, patients with the most active EGFR mutations in non-small cell lung cancer (NSCLC) have significantly benefited from EGFR tyrosine kinase inhibitors (TKIs). However, a minority with EGFR and HER2 exon 20 mutations are inherently resistant to treatment. Several molecular TKIs (such as TAK788 and Poziotinib) were recently discovered and demonstrated as effective inhibitors against the most prevalent HER2 or EGFR exon 20 mutations. However, low clinical efficiency and uncertain adverse reaction indicated that the development of effective therapies is still demanded. In the present work, we designed several hybrid compounds learning from 3D modeling of kinase structure. One lead compound (compound 56) was found to be the most potent compound with IC50 value of 0.027 nM against EGFR D770-N771 ins NPG and reduced binding affinity with hERG protein. In vitro and in vivo biological results suggested that compound 56 demonstrated good oral bioavailability, and it was significantly capable of inhibiting the growth of tumor cells with a variety of HER2 exon 20 mutations and EGFR mutants with negligible toxic effects. It was identified that compound 56 might be considered a potential drug candidate for NSCLC target therapy.
Insights
A novel compound, compound 56, shows potent inhibition against EGFR exon 20 mutations in non-small cell lung cancer (NSCLC). This potential drug candidate offers a promising targeted therapy with minimal toxicity for patients resistant to current treatments.
Area of Science:
- Oncology
- Medicinal Chemistry
- Pharmacology
Background:
- EGFR tyrosine kinase inhibitors (TKIs) benefit many non-small cell lung cancer (NSCLC) patients.
- A subset of NSCLC patients with EGFR and HER2 exon 20 mutations exhibit inherent resistance to existing TKIs.
- Existing molecular TKIs targeting these mutations show limited clinical efficacy and safety concerns.
Purpose of the Study:
- To design and identify novel hybrid compounds as potential targeted therapies for NSCLC.
- To develop effective inhibitors for EGFR and HER2 exon 20 mutations resistant to current treatments.
Main Methods:
- Utilized 3D modeling of kinase structures to design hybrid compounds.
- Synthesized and evaluated lead compounds for inhibitory activity against specific EGFR mutations.
- Assessed compound 56 for in vitro and in vivo efficacy, oral bioavailability, and toxicity.
Main Results:
- Compound 56 demonstrated high potency with an IC50 of 0.027 nM against EGFR D770-N771 ins NPG.
- Compound 56 exhibited reduced binding affinity with hERG protein, suggesting a favorable safety profile.
- In vitro and in vivo studies confirmed compound 56's ability to inhibit tumor growth in HER2 exon 20-mutated and EGFR mutant NSCLC with negligible toxicity.
Conclusions:
- Compound 56 is a potent inhibitor of key EGFR and HER2 exon 20 mutations in NSCLC.
- Compound 56 displays favorable pharmacokinetic properties and a promising safety profile.
- Compound 56 represents a potential drug candidate for targeted therapy in NSCLC patients with resistant mutations.
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