Identification of novel aminopyrimidine derivatives for the treatment of mutant NSCLC.

Starting from the binding mode of allosteric EGFR inhibitor JBJ-04-125-02 and the key pharmacophore of the third-generation EGFR inhibitors, we designed and synthesized a novel series of EGFR inhibitors, represented by (R)-N-(4-((2-aminopyrimidin-4-yl)amino)phenyl)-2-(5-(4-(4-methylpiperazin-1-yl)phenyl)-1-oxoisoindolin-2-yl)-2-phenylacetamide (6q). Docking study demonstrated that top compound 6q spanned orthosteric and allosteric sites of EGFR, and formed three key H-bonds with the residues Asp855, Lys745, and Met793 located in two sites. Biological evaluation indicated that compound 6q showed potential inhibitory activity against Ba/F3-EGFRL858R/T790M/C797S and Ba/F3-EGFRDel19/T790M/C797S cells, with IC50 values of 0.42 µM and 0.41 µM, respectively. Furthermore, compound 6q showed excellent activity against mutant NSCLC cell line NCI-H1975-EGFRL858R/T790M/C797S cells, with IC50 value of 0.82 µM which was superior to that of osimertinib (IC50 = 2.94 µM), JBJ-04-125-02 (IC50 = 3.66 µM), and coadministration of JBJ-04-125-02 and osimertinib (IC50 = 1.25 µM). Cell cycle arrest and cell apoptosis assay indicated that compound 6q could promote apoptosis of NCI-H1975-EGFRL858R/T790M/C797S cells at the concentration of 0.8 µM and no obvious cell cycle arrest was found.

Design, synthesis and biological evaluation of EGFR kinase inhibitors that spans the orthosteric and allosteric sites.

Acquired drug resistance occurred in the treatment of non-small-cell lung cancer is a persistent challenge, especially in EGFR mutant type. In this study, we present design, synthesis and biological evaluation of novel quinazoline and pyrrolopyrimidine derivatives that simultaneously occupy the orthosteric and allosteric sites of EGFR. Among them, compound A-7 was confirmed as a potential EGFRL858R/T790M/C797S and EGFRDel19/T790M/C797S inhibitor. Docking study indicated that compound A-7 could simultaneously occupy two binding sites of EGFR and form three key H-bonds with the residues Met793, Lys745 and Met766 in two regions.

Discovery of novel conjugates of quinoline and thiazolidinone urea as potential anti-colorectal cancer agent.

Based on the obtained SARs, further structural optimisation of compound BC2021-104511-15i was conducted in this investigation, and totally ten novel quinoline derivates were designed, synthesised and optimised for biological activity. Among them, compound 10a displayed significant in vitro anticancer activity against COLO 205 cells with an IC50 value of 0.11 µM which was over 90-fold more potent than that of Regorafenib (IC50>10.0 µM) and Fruquintinib (IC50>10.0 µM). Furthermore, compound 10a exhibited over 90-fold selectivity towards COLO 205 relative to human normal colorectal mucosa epithelial cell FHC cells. Flow cytometry study demonstrated that compound 10a could induce apoptosis in COLO 205 cells, however, it could not induce cell cycle arrest in COLO 205 cells. The results of preliminary kinase profile study showed that compound 10a was a potential HGFR and MST1R dual inhibitor, with IC50 values of 0.11 µM and 0.045 µM, respectively.

Identification of (S)-1-(2-(2,4-difluorophenyl)-4-oxothiazolidin-3-yl)-3-(4-((7-(3-(4-ethylpiperazin-1-yl)propoxy)-6-methoxyquinolin-4-yl)oxy)-3,5-difluorophenyl)urea as a potential anti-colorectal cancer agent.

In our previous study, 1-(2-(2,6-difluorophenyl)-4-oxothiazolidin-3-yl)-3-(4-((7-(3-(4-ethylpiperazin-1-yl)propoxy)-6-methoxyquinolin-4-yl)oxy)-3,5-difluorophenyl)urea (1) was obtained as a potent tyrosine kinase inhibitor. Further structural optimization was performed in this investigation, and a series of novel quinoline derivates were designed, synthesized and evaluated for their biological activity. Among them, compound 8m possessed nanomolar c-Met and Ron inhibitory activity, with IC50 values of 4.32 nM and 2.39 nM, respectively. Kinase profile study demonstrated that it could also inhibit ABL, PDGFRß, AXL, RET, and FLT3 with submicromolar potency. It also exhibited moderate to excellent cytotoxic activity against different types of human cancer cell lines, especially against COLO 205 cells (IC50 = 0.035 µM) which was remarkably superior to that of Cabozantinib (IC50 = 6.6 µM) and Fruquintinib (IC50 > 10.0 µM). Compared to ( ± )-8m, isomer (S)-8m and (R)-8m showed similar kinase inhibitory activity against c-Met/RON and in vitro anticancer activity against COLO 205 cells. Differently, compound (S)-8m showed an over 238-fold selectivity toward COLO 205 (IC50 = 0.042 µM) cells to FHC cells (IC50 > 10.0 µM), which indicated its low cytotoxicity against human normal tissue cells. Flow cytometry study demonstrated that compound (S)-8m could significantly induce apoptosis in COLO 205 cells in a dose-dependent manner. Cell cycle arrest assays showed that compound (S)-8m could not arrest the cell-cycle progression due to the massive dead cells.

Dual target inhibitors based on EGFR: Promising anticancer agents for the treatment of cancers (2017-).

The EGFR family play a significant role in cell signal transduction and their overexpression is implicated in the pathogenesis of numerous human solid cancers. Inhibition of the EGFR-mediated signaling pathways by EGFR inhibitors is a widely used strategy for the treatment of cancers. In most cases, the EGFR inhibitors used in clinic were only effective when the cancer cells harbored specific activating EGFR mutations which appeared to preserve the ligand-dependency of receptor activation but altered the pattern of downstream signaling pathways. Moreover, cancer is a kind of multifactorial disease, and therefore manipulating a single target may result in treatment failure. Although drug combinations for the treatment of cancers proved to be successful, the use of two or more drugs concurrently still was a challenge in clinical therapy owing to various dose-limiting toxicities and drug-drug interactions caused by pharmacokinetic profiles changed. Therefore, a single drug targeting two or multiple targets could serve as an effective strategy for the treatment of cancers. In recent, drugs with diverse pharmacological effects have been shown to be more advantageous than combination therapies due to their lower incidences of side effects and more resilient therapies. Accordingly, dual target-single-agent strategy has become a popular field for cancer treatment, and researchers became more and more interest in the development of novel dual-target drugs in recent years. In this review, we briefly introduce the EGFR family proteins and synergisms between EGFR and other anticancer targets, and summarizes the development of potential dual target inhibitors based on wild-type and/or mutant EGFR for the treatment of solid cancers in the past five years. Additionally, the rational design and SARs of these dual target agents are also presented in detailed, which will lay a significant foundation for the further development of novel EGFR-based dual inhibitors with excellent druggability.