New Antiproliferative Pyrazole/Quinoline Hybrids: Design, Synthesis, and Biological Evaluation as EGFR Inhibitors.

In present study, we have designed and developed some imidazo-thiadiazole based chalcone derivatives as potential EGFR inhibitors. The designed derivative were screened through molecular docking studies and subjected for synthesis followed by in vitro anticancer activity. Most interestingly many molecules had formed one Pi-donor hydrogen bond (Pi-sulfur) or conventional hydrogen bond with Cys797 which is mutated amino acid residue for the second generation EGFR inhibitors. Many molecules had formed Pi-sulfur bond with Met790 which is mutated amino acid residue and developed resistance to the third generation EGFR inhibitors. All the interaction results presented here suggest these molecule has potential to be developed as most potent 4th generation EGFR inhibitors which will might have effectiveness against triple mutant T790M/C797S EGFR. From this investigation, it was decided to synthesize all the designed molecules with their biological evaluation. In vitro cytotoxicity of synthesized compounds against MCF-7 (Breast cancer) and A549 (Lung cancer) cells were carried out using MTT assay. All the synthesized compounds induced the cytotoxicity to MCF-7 and A549 and displayed good range of IC50 values in between 4 to 59 µm/mL.

Herein, we report the discovery of a novel long-chain ether derivative of (−)-epigallocatechin-3-gallate (EGCG), a major green tea polyphenol as a potent EGFR inhibitor. A series of 4′′-alkyl EGCG derivatives have been synthesized via regio-selectively alkylating the 4′′ hydroxyl group in the D-ring of EGCG and tested for their antiproliferative activities against high (A431), moderate (HeLa), and low (MCF-7) EGFR-expressing cancer cell lines. The most potent compound, 4′′-C14 EGCG showed the lowest IC50 values across all the tested cell lines. 4′′-C14 EGCG was also found to be significantly more stable than EGCG under physiological conditions (PBS at pH 7.4). Further western blot analysis and imaging data revealed that 4′′-C14 EGCG induced cell death in A431 cells with shrunken nuclei, nuclear fragmentation, membrane blebbing, and increased population of apoptotic cells where BAX upregulation and BCLXL downregulation were observed. In addition, autophosphorylation of EGFR and its downstream signalling proteins Akt and ERK were markedly inhibited by 4′′-C14 EGCG. MD simulation and the MM/PBSA analysis disclosed the binding mode of 4′′-C14 EGCG in the ATP-binding site of EGFR kinase domain. Taken together, our findings demonstrate that 4′′-C14 EGCG can act as a promising potent EGFR inhibitor with enhanced stability.

Design and synthesis of 4,6-substituted-(diaphenylamino)quinazolines as potent EGFR inhibitors with antitumor activity

Novel quinazoline derivatives bearing various 6-benzamide moieties as highly selective and potent EGFR inhibitors

Epidermal growth factor receptor (EGFR, ErBb) belongs to family of receptor tyrosine kinase (RTKs) that plays an important role in multiple cell signaling pathways, which includes cell growth, multiplication apoptosis, etc. Overexpression of EGFR results in development of malignant cells. Therefore, EGFR is considered one of the important target for cancer therapy. In this study, virtual screening of 329 flavonoids obtained from the Naturally Occurring Plant-based Anti-cancer Compound-Activity-Target (NPACT) database had been performed to identify novel EGFR inhibitors. Virtual screening of flavonoids were carried out using different in silico methods, which includes molecular docking studies, prediction of druglikeness, in silico toxicity studies and bioactivity prediction. Six flavonoids NPACT00061, NPACT00062, NPACT00066, NPACT00280, NPACT00700 and NPACT00856 were identified as potential EGFR inhibitors with good docking score and druglikeness properties. In the in silico toxicity studies, compound NPACT00061, NPACT00062, NPACT00066 and NPACT00856 were found to be carcinogenic. Finally, two flavonoids NPACT00280 and NPACT00700 were recognized as novel EGFR inhibitors. Our findings suggest that compound NPACT00280 and NPACT00700 could be further explored as novel EGFR inhibitors.

Polygonatum odoratum lectin induces apoptosis and autophagy via targeting EGFR-mediated Ras-Raf-MEK-ERK pathway in human MCF-7 breast cancer cells

To design, synthesize, and evaluate novel pyrimidine-triazole derivatives as epidermal growth factor receptor (EGFR) inhibitors for anticancer activity. Ten derivatives (SM-1A to SM-1J) were synthesized and assessed for cytotoxicity against A549 lung cancer cell line also performed EGFR inhibition assay. Molecular docking was performed on the ATP binding pocket of EGFR (PDB: 1XKK). Compounds SM-1F and SM-1 G exhibited good cytotoxic activity (IC50 = 0.5 and 0.7 µM) than standard drug erlotinib (IC50 = of 0.9 µM). Compound SM-1F showed a good binding score -8.93 kcal/mol and interactions with amino acid residues THR 854, THR 790, CYS 775, and PHE856. The results showed SM-1F may be used as a lead compound for further development of novel EGFR inhibitors.

Treating patients suffering from EGFR mutant non-small cell lung cancer (NSCLC) with first-generation EGFR tyrosine kinase inhibitors (EGFR TKI) provides excellent response rates. However, approximately 60% of all patients ultimately develop drug resistance due to a second T790M EGFR TKI mutation. In this study, we report the novel molecule N-(3-((5-chloro-2-(4-((1-morpholino)methyl)phenylamino)-4-pyrimidinyl)amino)phenyl)acrylamide (DY3002) to preferentially inhibit the EGFR T790M mutant (EGFRT790M) (IC50 = 0.71 nM) over wild-type EGFR (IC50 = 448.7 nM) in kinase assays. Compared to rociletinib (SI = 21.4) and osimertinib (SI = 40.9), it significantly increased selectivity (SI = 632.0) against EGFRT790M over wild-type EGFR. Furthermore, in cell-based tests, DY3002, with an IC50 value of 0.037 μM, exhibited enhanced inhibitory potency against H1975 cells. Moreover, AO/EB and DAPI staining assays as well as flow cytometer analyses indicated that DY3002 possesses superior biological properties compared to alternatives. In addition, a rat oral glucose tolerance test revealed that treatment with high drug doses (50 mg/kg) of DY3002 did not result in hyperglycemia, suggesting a reduction of side effects in NSCLC patients will be achievable relative to established EGFR inhibitors. In summary, our findings indicate DY3002 as a promising preclinical candidate for effective treatment of patients with EGFRT790M-mutated NSCLC.

The indole backbone is encountered in a class of N-heterocyclic compounds with physiological and pharmacological effects such as anti-cancer, anti-diabetic, and anti-HIV. These compounds are becoming increasingly popular in organic, medicinal, and pharmaceutical research. Nitrogen compounds' hydrogen bonding, dipole- dipole interactions, hydrophobic effects, Van der Waals forces, and stacking interactions have increased their relevance in pharmaceutical chemistry due to their improved solubility. Indole derivatives, such as carbothioamide, oxadiazole, and triazole, have been reported to act as anti-cancer drugs due to their ability to disrupt the mitotic spindle and prevent human cancer cell proliferation, expansion, and invasion. To synthesize new 5-bromoindole-2-carboxylic acid derivatives that function as EGFR tyrosine kinase inhibitors as deduced through molecular docking studies. Different derivatives of indole (carbothioamide, oxadiazole, tetrahydro pyridazine-3,6-dione, and triazole) were synthesized and evaluated through different chemical, spectroscopic methods (IR, 1HNMR, 13CNMR, and MS) and assessed in silico and in vitro for their antiproliferative activities against A549, HepG2, and MCF-7 cancer cell lines. According to molecular docking analyses, compounds 3a, 3b, 3f, and 7 exhibited the strongest EGFR tyrosine kinase domain binding energies. In comparison to erlotinib, which displayed some hepatotoxicity, all of the evaluated ligands displayed good in silico absorption levels, did not appear to be cytochrome P450 inhibitors, and were not hepatotoxic. The new indole derivatives were found to decrease cell growth of three different types of human cancer cell lines (HepG2, A549, and MCF-7), with compound 3a being the most powerful while still being cancer-specific. Cell cycle arrest and the activation of apoptosis were the results of compound 3a's inhibition of EGFR tyrosine kinase activity. The novel indole derivatives, compound 3a in particular, are promising anti-cancer agents which inhibit cell proliferation by inhibiting EGFR tyrosine kinase activity.

Novel thienopyrimidinone hybrids 5-25 were developed and synthesized as potential inhibitors of human EGFR and FGFR. The in vitro antiproliferative action of all compounds, towards the human breast tumor cells MDA-MB-231 and MCF-7, was evaluated with doxorubicin serving as a reference (IC50 = 6.72 µM). Compound 23 demonstrated the highest anti-breast cancer efficacy against both cellular lines having IC50 ranging from 2.95 to 3.80 µM. The enzyme inhibition of human EGFR and FGFR by the most active candidates 18, 21and 23-25 was further evaluated. Compounds 21 and 25 were the best EGFR inhibitors having IC50 values of 0.077 and 0.059 µM, respectively, in comparison to Erlotinib (IC50 = 0.04 µM). In comparison with Staurosporine (IC50 = 0.024 µM), compounds 24 and 25 were the most active FGFR inhibitors having IC50 values of 0.055 and 0.029 µM, respectively. The study of molecular docking was carried out among the most active EGFR inhibitors 21 and 25 and the most active FGFR inhibitors 24 and 25 to examine the relation between the binding pattern of these compounds with EGFR and FGFR catalytic active sites and their biological activity, whereas the computational results were aligned with the biological results. Finally, compound 25, which was found to be the best dual inhibitor against EGFR and FGFR, was tested for inducing apoptosis and affecting cellular arrest within G2/M phase as well as it was screened to measure its safety towards normal breast cells MCF10a with IC50 value of 47.16 µM in contrast to the reference Staurosporine (IC50 = 18.86 µM). Accordingly, compound 25 could be considered as a potential breast cancer therapy.

The present study explores the potential of the new sulfonamide derivatives coupled with salicylamide or anisamide scaffold as immune checkpoint PD-L1 inhibitors. Based on in silico virtual screening 32 derivatives were synthesized and tested in vitro as PD-L1 inhibitors using screening ELISA assay. Five compounds gave promising results with more than 50% inhibition. The most active, with activity 57.152%, was 5-Chloro-N-(4-(N-(3-fluorophenyl)sulfamoyl)phenethyl)salicylamide (30). The other compounds were 5-Chloro-2-methoxy-N-(4-(N-(4-fluorophenyl)sulfamoyl)benzyl)benzamide (4, 53.327%), 5-Chloro-2-methoxy-N-(4-(N-(4-methylphenyl)sulfamoyl)phenethyl)benzamide (17, 51.253%), 5-Chloro-N-(4-(N-(4-(trifluoromethyl) phenyl)sulfamoyl)phenethyl)salicylamide (31, 51.058%) and 5-Chloro-2-methoxy-N-(4-(N-(2,4-difluorophenyl)sulfamoyl) benzyl)benzamide (7, 50.993). The synthesized compounds were tested for potential anti-proliferative activity against some cell lines to evaluate the safety of PD-L1 active compounds and compare their anti-proliferative activity with that of other compounds under investigation. All compounds were found to be safe and did not have any cytotoxic effects on the fibroblast cell lines. Moreover, compounds 4, 7, 17, and 30 showed little to no anti-proliferative activity against the cell lines used in this study except compound 4, which displayed anti-proliferative activity against PC-3 (66.640%). On the other hand, compound 31 showed remarkable activities against the cell lines MCF-7, DU-145, and PC-3. Human prostate cancer cell line PC-3 is highly sensitive to some of the 32 compounds tested at 10 μM. The molecular docking study and ADMET analysis of the bioactive compounds were used to elucidate the mode-of-action mechanism.

Design, synthesis, and biological evaluation of novel aminopyrimidine derivatives as EGFR inhibitors.

374P NX-019, a brain penetrant, mutation selective EGFR inhibitor with broad mutant EGFR activity

Design, synthesis and biological evaluation of 2-amino-4-(1,2,4-triazol)pyridine derivatives as potent EGFR inhibitors to overcome TKI-resistance

Quinoline-based thiazolidinone heterocycles exhibited potent activity in the field of cancer therapy. Hence, ten quinoline-based thiazolidinone derivatives were evaluated for their anticancer activity through cytotoxic activity, epidermal growth factor receptor (EGFR) inhibition pathway, apoptosis investigation through flow cytometric analyses, RT-PCR gene expression, in vivo solid-Ehrlich carcinoma model, and finally in silico approach for highlighting the interaction pose. Results revealed that compound 7 exhibited cytotoxic activity against HCT-116 cells with an IC50 value of 7.43µM compared to 5-FU (IC50 =11.36µM) with moderate cytotoxic activity against the FHC (IC50 =35.27µM), and it exhibited remarkable inhibition activity of EGFR with IC50 value of 96.43nM compared to Erlotinib (IC50 =78.65nM). Moreover, it significantly stimulated apoptotic colon cancer cell death with 171.58-fold arresting cell cycle at G2 and S-phases. Additionally, it ameliorated both biochemical and histochemical structures near normal with tumor inhibition ratio of 52.92% compared to 5-FU of 57.16%, with immunohistochemical examinations of EGFR inhibition in the treated group compared to control. Finally, molecular docking study highlighted its good binding affinity through good interactive binding pose inside the EGFR protein. In conclusion, the potent EGFR inhibitory activity of compound 7 was investigated using three integrated approaches in vitro, in vivo, and in silico, so it worth be validated and developed as a chemotherapeutic anticancer agent.