Probing Dual Covalent Irreversible Inhibition of EGFR/FGFR4 by Electrophilic-Based Natural Compounds to Overcome Resistance and Enhance Combination Therapeutic Potentials and Management of Hepatocellular Carcinoma (HCC)

IF 1.9 4区 生物学 Q4 BIOCHEMISTRY & MOLECULAR BIOLOGY
Huimin Xue, Peng Chen, Jingyi Jiao, Xiaojun Zhu
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引用次数: 0

Abstract

Hepatocellular carcinoma (HCC) is one of the most prevalent cancer types in the world and accounts for the majority of cases of primary liver cancer. A crucial part of the carcinogenesis of HCC involves aberrant stimulation of the FGF19-FGFR4 signaling pathway. Therefore, FGFR4 inhibition has become a strategic therapeutic approach for the treatment of HCC. However, the clinical treatment procedure is significantly hampered by the prevalence of kinase inhibitors resistance. It was recently established that the activation of EGFR signaling was found to be one of the primary mechanisms mediating the acquired resistance to FGFR4 inhibitors, moreover, sensitivity to FGFR4 inhibitors was effectively restored by inhibiting EGFR. These results provide compelling evidence that dual inhibition of EGFR and FGFR4 could represent a viable therapeutic approach to overcome resistance, hence enhanced management of HCC. To this end, we proposed a dual irreversible inhibition strategy through covalent binding by naturally occurring electrophilic warhead-bearing compounds (curcumin, deoxyelephantopin, eupalmerin acetate, syringolin A and andrographolide) to covalently target both EGFR and FGFR4 through cysteine residues, Cys797 and Cys552, respectively. Covalent docking and covalent molecular dynamics (MM/MDcov) simulations combined with thermodynamic binding free energy calculations were performed, and the results were compared against known potent and selective covalent EGFR and FGFR4 inhibitors with available X-ray crystal structures, Afatinib and BLU9931, respectively. Curcumin, deoxyelephantopin, eupalmerin acetate, syringolin A, and andrographolide showed relative binding free energies of -22.85, -17.14, -12.98, -21.81, and − 19.00 kcal/mol against EGFR and − 41.06, -29.45, -24.76, -40.11, and − 37.55 kcal/mol against FGFR4, respectively. The mechanisms of binding were emphasized by hydrogen bonding and binding forces analysis as well as active site physicochemical profiling. The findings of this study identified that curcumin, syringolin A and andrographolide—but not eupalmerin acetate or deoxyelephantopin —could be viable dual EGFR and FGFR4 covalent irreversible inhibitors and could be implemented in HCC combination therapy protocols alone or in conjunction with other chemotherapeutic agents. Investigations of this study conclusively indicate dual blockade of EGFR and FGFR4 may be a promising future therapeutic strategy for enhanced management of HCC.

Abstract Image

探究亲电天然化合物对表皮生长因子受体/表皮生长因子受体4的双共价不可逆抑制作用,以克服抗药性并增强联合治疗的潜力和对肝细胞癌(HCC)的治疗。
肝细胞癌(HCC)是世界上发病率最高的癌症类型之一,占原发性肝癌病例的大多数。HCC 癌变的关键部分涉及 FGF19-FGFR4 信号通路的异常刺激。因此,抑制 FGFR4 已成为治疗 HCC 的战略疗法。然而,激酶抑制剂耐药性的普遍存在严重阻碍了临床治疗进程。最近有研究发现,表皮生长因子受体(EGFR)信号的激活是FGFR4抑制剂获得性耐药的主要机制之一,而且通过抑制表皮生长因子受体可有效恢复对FGFR4抑制剂的敏感性。这些结果提供了令人信服的证据,表明对表皮生长因子受体和表皮生长因子受体4的双重抑制可能是克服耐药性的可行治疗方法,从而提高对HCC的治疗效果。为此,我们提出了一种不可逆的双重抑制策略,即通过天然亲电弹头化合物(姜黄素、脱氧叶黄素、醋酸玉兰脂素、丁香油素 A 和穿心莲内酯)的共价结合,分别通过半胱氨酸残基 Cys797 和 Cys552 共价靶向表皮生长因子受体和表皮生长因子受体 4。研究人员结合热力学结合自由能计算,进行了共价对接和共价分子动力学(MM/MDcov)模拟,并将结果与已知的具有X射线晶体结构的强效和选择性共价表皮生长因子受体(EGFR)和表皮生长因子受体(FGFR4)抑制剂阿法替尼(Afatinib)和BLU9931进行了比较。姜黄素、脱氧鸭跖草素、醋酸玉竹素、丁香油酚 A 和穿心莲内酯对表皮生长因子受体的相对结合自由能分别为 -22.85、-17.14、-12.98、-21.81 和 - 19.00 kcal/mol,对表皮生长因子受体 4 的相对结合自由能分别为 -41.06、-29.45、-24.76、-40.11 和 - 37.55 kcal/mol。氢键和结合力分析以及活性位点理化分析强调了结合机制。本研究的结果表明,姜黄素、丁香油酚 A 和穿心莲内酯(而非醋酸优降宁或脱氧苦参碱)是可行的表皮生长因子受体和表皮生长因子受体 4 双共价不可逆抑制剂,可单独或与其他化疗药物一起用于 HCC 联合治疗方案。本研究的调查结果表明,表皮生长因子受体(EGFR)和表皮生长因子受体(FGFR)4的双重阻断可能是未来治疗HCC的一种有前途的治疗策略。
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来源期刊
The Protein Journal
The Protein Journal 生物-生化与分子生物学
CiteScore
5.20
自引率
0.00%
发文量
57
审稿时长
12 months
期刊介绍: The Protein Journal (formerly the Journal of Protein Chemistry) publishes original research work on all aspects of proteins and peptides. These include studies concerned with covalent or three-dimensional structure determination (X-ray, NMR, cryoEM, EPR/ESR, optical methods, etc.), computational aspects of protein structure and function, protein folding and misfolding, assembly, genetics, evolution, proteomics, molecular biology, protein engineering, protein nanotechnology, protein purification and analysis and peptide synthesis, as well as the elucidation and interpretation of the molecular bases of biological activities of proteins and peptides. We accept original research papers, reviews, mini-reviews, hypotheses, opinion papers, and letters to the editor.
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