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Anti-Cancer Agents in Medicinal Chemistry

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ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

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Research Article

Novel Potent EGFR-JAK3 Dual-Target Inhibitor that Overcomes KRAS Mutation Resistance in Colorectal Cancer

Author(s): Tingyu Wu, Jiawen Yu, Changyuan Wang, Yue Jin, Xu Zheng, Lixue Chen*, Xiaodong Ma* and Xiuli Sun*

Volume 23, Issue 4, 2023

Published on: 20 August, 2022

Page: [440 - 449] Pages: 10

DOI: 10.2174/1871520622666220609112816

Price: $65

Abstract

Background: In-depth and clear mechanistic study is a prerequisite for new drugs to enter clinical research.

Methods: New chemical entity BY4008 was identified by our lab as a novel and highly potent EGFR and JAK3 dualtarget inhibitor. A cell-based test exhibited strong antiproliferative activities against SW620 and HCT116 colon cancer cells harboring KRAS mutation with IC50 of nanomolar potency. Furthermore, acridine orange/ethidium bromide (AO/EB), Hematoxylin-Eosin (H&E) and DAPI staining assays and flow cytometry analyses indicated that BY4008 has the function of pro-apoptosis and arresting the cell cycle. In addition, BY4008 inhibited the autophosphorylation of EGFR and blocked the activation of downstream signaling and the JAK-STAT3 pathway.

Results: Meanwhile, a decreased level of reactive oxygen species (ROS) and an increased level of malondialdehyde (MDA) in SW620 and HCT116 cells were observed after exposure to BY4008.

Conclusion: In summary, this study provides an important structural basis and mechanistic study for future effective treatment of colorectal cancer.

Keywords: EGFR, JAK3, KRAS mutation, colorectal cancer, dual-target inhibitor, clinical research.

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