Discovery of novel Quinazoline based Thiazolotriazole hybrids as potential EGFR inhibitor: Synthesis, anticancer evaluation and in silico studies

Design, synthesis, and mechanistic insight of novel imidazolones as potential EGFR inhibitors and apoptosis inducers

EGFR tyrosine kinase inhibitor: design, synthesis, characterization, biological evaluation, and molecular docking of novel 1,3,4-oxadiazole, thio-methyl, and 1,2,3-triazole hybrids

The strategic planning of this study is based upon using the nanoformulation method to prepare nanoparticles 4-SLNs and 4-LPHNPs of the previously prepared 4,5-diphenyl-1H-pyrazolo[3,4-c]pyridazin-3-amine (4) after confirming its structure with single crystal X-ray analysis. These nanoparticles exhibited promising cytotoxic activity against HepG-2, HCT-116 and MCF-7 cancer cell lines in comparison with the reference doxorubicin and the original derivative 4. Moreover, their inhibitory assessment against EGFR and CDK-2/cyclin A2 displayed improved and more favorable impact than the parent 4 and the references. Detection of their influence upon cancer biomarkers revealed upregulation of Bax, p53 and caspase-3 levels and downregulation of Bcl-2 levels. The docking simulation demonstrated that the presence of the pyrazolo[3,4-c]pyridazin-3-amine scaffold is amenable to enclosure and binding well within EGFR and CDK-2 receptors through different hydrophilic interactions. The pharmacokinetic and physicochemical properties of target 4 were also assessed with ADME investigation, and the outcome indicated good drug-like characteristics.

Design, synthesis, crystal structures and biological evaluation of some 1,3-thiazolidin-4-ones as dual CDK2/EGFR potent inhibitors with potential apoptotic antiproliferative effects

Design, synthesis and biological evaluation of pyrazolyl-thiazolinone derivatives as potential EGFR and HER-2 kinase inhibitors

Design, synthesis and biological evaluation of thiazolidinone derivatives as potential EGFR and HER-2 kinase inhibitors

3-Substituted-2,3-Dihydrothiazole as a promising scaffold to design 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.

Synthesis and in vitro anticancer evaluation of some fused indazoles, quinazolines and quinolines as potential EGFR inhibitors

Τhe Epidermal Growth Factor Receptor tyrosine kinase inhibitor (EGFR-TKI) 6-amino-4-[(3-bromophenyl) amino]quinazoline was derivatized with 6-bromohexanoyl-chloride and coupled with the tridentate chelating agents N-(2-pyridylmethyl) aminoethyl acetic acid (PAMA) and L(+)-cysteine bearing the donor atom set NNO and SNO, respectively. The rhenium precursors ReBr(CO)5 and fac-[NEt4]2[ReBr3(CO)3] were used for the preparation of the Re complexes fac-[Re(NNO)(CO)3] (5a) and fac-[Re(SNO)(CO)3] (7a) which were characterized by NMR and IR spectroscopies. Subsequently, the new potential EGFR inhibitors were labeled with the fac-[99mTc(CO)3]+ core in high yield and radiochemical purity (>90%) by ligand exchange reaction using the fac-[99mTc][Tc(OH2)3(CO)3]+ precursor. The radiolabeled complexes were characterized by comparative HPLC analysis with the analogous rhenium (Re) complexes as references. In vitro studies in the A431 cell lines showed that both ligands and Re complexes inhibit A431 cell growth. Complex 5a demonstrated the highest potency (IC50 = 8.85 ± 2.62 μM) and was further assessed for its capacity to inhibit EGFR autophosphorylation, presenting an IC50 value of 26.11 nM. Biodistribution studies of the 99mTc complexes in healthy mice showed high in vivo stability for both complexes and fast blood and soft tissue clearance with excretion occurring via the hepatobiliary system.

A novel series of benzo[d]thiazole-2-carboxamide derivatives have been de novo designed based on virtual screening methods. The target compounds were synthesized and evaluated for the cytotoxicity against epidermal growth factor receptor high-expressed cancer cell lines (A549, HeLa, and SW480), epidermal growth factor receptor low-expressed cell line (HepG2) and human liver normal cell line (HL7702). Several target compounds have showed moderate to excellent potency against A549, HeLa, and SW480 and weak cytotoxic effects against HepG2, which implies they are probably epidermal growth factor receptor inhibitors. And scarcely did they exhibit any activities against HL7702, which signifies they are likely to overcome the nonspecific toxicity against normal cells. Especially, the compound 6-[2-(diethylamino)-2-oxoethoxy]-N-(furan-2-ylmethyl)benzo[d]thiazole-2-carboxamide (6i) was identified as a promising agent, exhibiting the most potent cytotoxic activities with IC50 values of 4.05, 12.17, 6.76 μM against the A549, HeLa, and SW480 cell lines, respectively.

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.

The mutations concerned with non-small cell lung cancer involving epidermal growth factor receptor of tyrosine kinase family have primarily targeted. EGFR inhibitors binding allosterically to C797S mutant EGFR enzyme have been developed. Here, database building, library screening performing R-group enumeration and scaffold hopping technique for increasing the EGFR binding affinity of compounds have been carried out. Virtual screening was performed subjecting to HTVS, SP and XP docking protocol along with its relative binding free energy calculations. Molecular docking studies provided the information about binding pockets and interactions of molecules on mutant (PDB: 5D41) as well as wild type (PDB: 4I23) EGFR enzyme. This was supported with ADMET and molecular simulation studies. On the basis of glide score and protein-ligand interactions, highest scoring molecule was selected for molecular dynamic simulation providing a complete insight into the conformational stability. The virtually screened molecules can act as potential EGFR inhibitors in the management of drug resistance. Communicated by Ramaswamy H. Sarma

Epidermal growth factor receptor (EGFR) inhibitors are commonly utilized in treating cancers such as non‐small cell lung cancer (NSCLC). However, the emergence of resistance often reduces their long‐term effectiveness, prompting an urgent need for novel inhibitors. In this study, we designed and assessed a series of amino acid‐functionalized 2,5‐diketopiperazine (DKP) derivatives as potential EGFR inhibitors using molecular docking and dynamics simulations. Ten analogs were docked against the EGFR kinase domain (PDB ID: 1M17), exhibiting binding energies ranging from −8.88 to −10.26 kcal/mol. For comparison, Erlotinib and Doxorubicin showed binding energies of −7.05 and −10.23 kcal/mol, respectively. Notably, compound 10 demonstrated a lower binding energy than both reference compounds, indicating strong binding affinity and favorable interactions with key residues such as Met769. Furthermore, molecular dynamics simulations over 100 nanoseconds, including analyses of RMSD, RMSF, radius of gyration (Rg), and hydrogen bonding patterns, revealed that compounds 3, 5, and 10 maintained structural stability and consistent interactions throughout the simulations. These findings highlight the potential of amino acid‐functionalized 2,5‐DKP‐based compounds as next‐generation EGFR inhibitors, setting the stage for future experimental validation and therapeutic exploration.

To overcome T790M mutation, a novel series of 4-indazolypyrimidine derivatives were developed as novel EGFR inhibitors employing a scaffold hopping drug design strategy. The biological activities of the target compounds were evaluated against two tumor cell lines (A431 and NCI-H1975), normal cell 2BS and EGFRT790M/L858R kinase. The results indicated that the majority of the compounds exhibited promising antitumor activity and low toxicity. Specifically, compounds 4e and 4s displayed the highest efficacy, with IC50 values of 0.55μM and 0.47μM, respectively. Moreover, compounds 4e and 4s demonstrated exceptional activity against EGFRT790M/L858R, with IC50 values of 12.04 and 28.79nM. Additionally, further studies revealed that compounds 4e and 4s could induce apoptosis in NCI-H1975 cells and arrest the cells in the G2/M phase. Molecular docking studies revealed that compounds 4e and 4s could interact closely with EGFR. These findings lay the groundwork for further investigation of compounds 4e and 4s as potential EGFR inhibitors.