EGFR and COX-2 Dual Inhibitor: The Design, Synthesis, and Biological Evaluation of Novel Chalcones

Abstract

For most researchers, discovering new anticancer drugs to avoid the adverse effects of current ones, to improve therapeutic benefits and to reduce resistance is essential. Because the COX-2 enzyme plays an important role in various types of cancer leading to malignancy enhancement, inhibition of apoptosis, and tumor-cell metastasis, an indispensable objective is to design new scaffolds or drugs that possess combined action or dual effect, such as kinase and COX-2 inhibition. The start compounds A1 to A6 were prepared through the diazo coupling of 3-aminoacetophenone with a corresponding phenol and then condensed with two new chalcone series, C7–18. The newly synthesized compounds were assessed against both COX-2 and epidermal growth factor receptor (EGFR) for their inhibitory effect. All novel compounds were screened for cytotoxicity against five cancer cell lines. Compounds C9 and G10 exhibited potent EGFR inhibition with IC50 values of 0.8 and 1.1 µM, respectively. Additionally, they also displayed great COX-2 inhibition with IC50 values of 1.27 and 1.88 µM, respectively. Furthermore, the target compounds were assessed for their cytotoxicity against pancreatic ductal cancer (Panc-1), lung cancer (H-460), human colon cancer (HT-29), human malignant melanoma (A375) and pancreatic cancer (PaCa-2) cell lines. Interestingly, compounds C10 and G12 exhibited the strongest cytotoxic effect against PaCa-2 with average IC50 values of 0.9 and 0.8 µM, respectively. To understand the possible binding modes of the compounds under investigation with the receptor cites of EGFR and COX-2, a virtual docking study was conducted.

The role of lipid metabolic reprogramming in tumor microenvironment

“…However, they are beneficial only when combined with chemotherapy drugs or immune checkpoint inhibitors (ICIs). Notably, the EGFR signaling pathway reduces the expression of intracellular 15-PGDH; therefore, the combined blocking effect of EGFR and COX-2 may also enhance the antitumor effect of COX-2 inhibitors 260 . In addition, the expression of indoleamine 2, 3-dioxygenase 1, an important immunomodulatory enzyme in tumor cells, is related to the activation of the COX2/PGE2 axis; therefore, COX-2 inhibitors can enhance the effect of the anti-PD-1 therapy to some extent 261 .…”

Fe2O3 Embedded in N-Doped Porous Carbon Derived from Hemin Loaded on Active Carbon for Supercapacitors

“…The FT-IR spectra of the samples are displayed in Figure 2 b. All samples exhibited wide peaks from 3400 to 3500 cm −1 (shaded regions), caused by the stretching vibrations of O=C–OH and –OH [ 28 ]. The IR spectrum of Hemin/AC retained the characteristic peaks of Hemin, indicating that the molecular structure of Hemin was intact.…”

A Narrative Review on Therapeutic Potential of Fisetin in Colorectal Cancer: Focusing on apoptosis and biochemical processes

“…While COX2 stands out as a promising target for CRC therapy and prevention, the extended use of COX2 inhibitors is constrained by associated cardiovascular side effects [96]. Furthermore, COX2 exerts downstream effects on the EGFR pathway, a critical player in colon carcinogenesis, suggesting that dual targeting of COX2 and EGFR may enhance cancer suppression [97,98]. Suh et al investigated the therapeutic potential of fisetin in treating colon cancer, revealing its capability to effectively downregulate β-catenin and COX2, providing a strong foundation for further exploration.…”