3-Substituted-2,3-Dihydrothiazole as a promising scaffold to design EGFR inhibitors
Radwan El-Haggar1, Sherif F Hammad2, Reem I Alsantali3
1Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Helwan University, Ain Helwan 11795, Cairo, Egypt; Institut des Biomolécules Max Mousseron (IBMM), UMR 5247, CNRS, Université de Montpellier, ENSCM, 34293 Montpellier, France.
Abstract:
The overexpression of EGFR has been recognized as the driver mechanism in the development of several human malignancies and the clinical use of EGFR inhibitors currently constitutes the standard of care for a wide range of malignancies, including colorectal cancer. However, the clinical efficacy of EGFR targeted inhibitors is limited by the development of intrinsic or acquired resistance, requiring the discovery of new compounds with different structural characteristics from those already developed. In this context, we explored the replacement of the aminoquinazoline pharmacophore of several FDA-approved EGFR inhibitors by its bioisosteric hydrazinothiazole moiety. A series of 14 new compounds were designed, synthesized, and evaluated as potential EGFR inhibitors. Compound 5i was active against 12 different cell lines in the NCI-60 cell line panel and showed an IC50 of 6.9 ± 0.013 µM against HCT-116 cells, with no significant toxicity against normal human fibroblasts (WI-38). Further studies showed that this compound showed submicromolar activity against EGFR and was able to induce tumor cell cycle arrest and cell apoptosis. Additionally, docking experiments, molecular dynamics and binding free energy calculations were performed and confirmed the potential of 2-hydrazino-2,3-dihydrothiazole derivatives as new EGFR inhibitors.
Insights
New EGFR inhibitors based on a hydrazinothiazole scaffold show promise for cancer treatment. Compound 5i effectively inhibited cancer cell growth and induced apoptosis, offering a potential alternative to existing therapies.
Area of Science:
- Oncology
- Medicinal Chemistry
- Molecular Biology
Background:
- Epidermal Growth Factor Receptor (EGFR) overexpression drives multiple human cancers.
- EGFR inhibitors are standard care but face resistance issues.
- Novel EGFR inhibitors are needed to overcome resistance.
Purpose of the Study:
- To design and synthesize novel EGFR inhibitors.
- To replace the aminoquinazoline core with a bioisosteric hydrazinothiazole moiety.
- To evaluate the anticancer potential of new derivatives.
Main Methods:
- Synthesis of 14 novel compounds.
- In vitro evaluation against the NCI-60 cell line panel.
- Biochemical assays for EGFR inhibition.
- Cell cycle arrest and apoptosis induction studies.
- Computational studies including docking and molecular dynamics.
Main Results:
- Compound 5i demonstrated broad activity against 12 cell lines.
- Compound 5i showed an IC50 of 6.9 µM against HCT-116 cells with low toxicity to normal fibroblasts.
- Submicromolar EGFR inhibition was observed for compound 5i.
- Compound 5i induced tumor cell cycle arrest and apoptosis.
- Computational analyses supported the inhibitory potential of the novel derivatives.
Conclusions:
- 2-hydrazino-2,3-dihydrothiazole derivatives represent a promising new class of EGFR inhibitors.
- Compound 5i exhibits significant anticancer activity and warrants further investigation.
- This scaffold offers a potential strategy to overcome resistance to existing EGFR inhibitors.
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