Here, we highlight the synthesis of a number of novel pyridine/thiazole hybrids 1 to 6a,b and their screening as possible anticancer drugs through dual targeting of VEGFR-2 and EGFR. The novel compounds were created in accordance with the structural specifications of the target receptors. The MTT assay was used to assess the compounds' cytotoxicity against the cancer cell lines HepG2, MCF-7, HCT116, and A549. With IC50 values of 6.50, 7.00, 5.55, and 6.85 μM against HepG2, MCF-7, A549, and HCT116 cell lines, respectively, compound 5b demonstrated the strongest anticancer activity. Although it was less effective than sorafenib against the studied cell lines, it was more effective than erlotinib against HepG2, MCF-7, and HCT116, while it was less effective against A549. The six potent compounds 4a, 4b, 4c, 5a, 5b, 6a, and 6b were assessed for their toxic effects on VERO normal cell lines to determine cytotoxicity levels. Results across all studies indicated that every synthesized compound demonstrated minimal toxicity toward VERO normal cells, with IC50 values ranging between 47.60 and 52.22 μM. Additionally, molecular modeling studies were used to investigate how well the novel derivatives could interact with EGFR and VEGFR-2 receptors. Furthermore, the compounds underwent additional testing to measure their capacity to inhibit both EGFRT790M and VEGFR-2. Compounds 5b, 4b, 4c, and 6b demonstrated excellent inhibitory potency against VEGFR-2, exhibiting IC50 values of 0.95, 1.00, 1.15, and 1.35 μM, respectively. Also, compounds 5b, 4c, 4b, and 6b inhibited EGFRWT activity with IC50 = 0.24, 0.30, 0.37 and 0.40 μM respectively. Similarly, these same compounds displayed superior inhibitory effects on EGFRT790M, with corresponding IC50 values of 0.26, 0.36, 0.44, and 0.50 μM, respectively. Notably, derivatives 5b, 4b, and 4c exhibited good in silico ADMET predictions.
N. Ahmed, Rizk E. Khidre, Mohamed R. Khidre et al.· Bioorganic chemistry (Print)· 0 citations
The development of the C797S resistance mutation to third-generation tyrosine kinase inhibitors in EGFR-mutant non-small cell lung cancer is a key therapeutic barrier, and this renders standard orthosteric site competitive inhibitors futile. Allosteric inhibitors of EGFR have emerged as a promising strategy for overcoming this resistance mechanism due to a structurally distinct binding site approximately 15-20 Å from the C797S mutation that confers potency independent of the status of cysteine-797. This comprehensive review summarizes the last decade of allosteric EGFR inhibitor medicinal chemistry, including 185 compounds across eight scaffold classes representing the entire reported landscape of efforts toward targeting EGFR with small molecules allosterically. The aminothiazole scaffold dominates the field with 57 compounds, followed by 4-anilinoquinazoline with 39 compounds; the focus of the field is concentrated on these privileged scaffolds. Five universal design principles governing allosteric potency have been identified through structure-activity relationship analysis: the formation of a hydrogen bond network, complementarity to a hydrophobic pocket, bivalent binding architecture based on a dual heterocycle, precise linker geometry, and core heterocycle identity. These principles account for the spectacular potency achievements that include 11 compounds reaching ultra-nanomolar potency (IC₅₀ < 1 nM) and 54 compounds attaining single-digit nanomolar activity. The aminothiazole-isoindolinone hybrid attained the most potent compound 4 with 0.10 nM, which is 20-fold, improved from the foundational EAI045 compound. The maturity of the field peaked in 2022 in optimization efforts, with 85 compounds reported. This review establishes that allosteric EGFR inhibition represents a clinically viable strategy for addressing osimertinib resistance, with lead candidates ready for clinical translation.
Ibrahim Mohammed Hepishy, Mo'men Salem, Ahmed El-morsy et al.· Bioorganic chemistry (Print)· 0 citations
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