인문학
사회과학
자연과학
공학
의약학
농수해양학
예술체육학
복합학
DBpia AI
AI 에이전트
AI 아이디어
AI 리더
AI 뷰어
Citeasy
크롬 서지관리 다운로드
지원사업
학술연구/단체지원/교육 등 연구자 활동을 지속하도록 DBpia가 지원하고 있어요.
커뮤니티
연구자들이 자신의 연구와 전문성을 널리 알리고, 새로운 협력의 기회를 만들 수 있는 네트워킹 공간이에요.
초록·키워드
This study focused on the design and synthesis of a novel series of 5-ethylsulfonyl-indazole-3-carboxamides (8a-l) as dual inhibitors of VEGFR-2 and EGFR. Compounds 8g and 8h emerged as the most efficient derivatives among all evaluated compounds against breast (MCF-7) and colorectal (HCT-116) cancer cell lines, exhibiting IC<sub>50</sub> values of 24 and 28 nM for HCT-116 and MCF-7 cell lines, respectively, for 8g, and 23 and 25 nM for the same cell lines for 8h. Compounds 8g and 8h exhibited a promising safety margin against normal cells (WI-38) (IC<sub>50</sub> values > 150 nM). <i>In vitro</i> enzyme assays demonstrated that compounds 8g and 8h exhibited potent inhibition of VEGFR-2 and EGFR. Furthermore, compounds 8g and 8h induced apoptosis by activating Bax, p53, caspase-3, 8, and 9, as well as down-regulating Bcl-2. Compounds 8g and 8h reduced TNF-α and IL-6 levels compared to dexamethasone. The computational investigation of compound 8h, a novel indazole-based urea derivative, was undertaken to rationalize its potent dual inhibition of EGFR and VEGFR-2. Molecular docking studies revealed a high binding affinity and a favorable interaction profile with key kinase residues, particularly hinge-region contacts with Met769 (EGFR) and Glu885/Asp1046 (VEGFR-2). Follow-up molecular dynamics (MD) simulations confirmed the stability of the 8h-EGFR complex over 150 ns, characterized by persistent hydrogen bonding, low RMSF in the binding site, and consistent radius of gyration. Quantum mechanical (QM) analyses, including DFT and MEP mapping, revealed a HOMO-LUMO gap of 4.55 eV, high dipole moment (9.3 D), and distinct electron-rich/hydrogen-bonding regions, supporting strong molecular interactions. Additionally, SwissADME profiling demonstrated acceptable drug-likeness, moderate solubility, and a low CYP-inhibition profile, suggesting favorable pharmacokinetics compared to the reference inhibitor erlotinib. These integrated computational findings align with experimental data on antiproliferative effects and kinase inhibition, reinforcing compound 8h as a promising dual-target anticancer candidate.
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오류를 발견하셨다면 해당 부분을 드래그한 후 ' 를 통해 신고해주세요.
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