Lawal Bashir, Lee Ching-Yu, Mokgautsi Ntlotlang, Sumitra Maryam Rachmawati, Khedkar Harshita, Wu Alexander T H, Huang Hsu-Shan
PhD Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei, Taiwan.
Graduate Institute for Cancer Biology & Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
Front Oncol. 2021 Mar 26;11:656738. doi: 10.3389/fonc.2021.656738. eCollection 2021.
The application of computational and multi-omics approaches has aided our understanding of carcinogenesis and the development of therapeutic strategies. NSC765598 is a novel small molecule derivative of salicylanilide. This study aims to investigate the ligand-protein interactions of NSC765598 with its potential targets and to evaluate its anticancer activities
We used multi-computational tools and clinical databases, respectively, to identify the potential drug target for NSC765598 and analyze the genetic profile and prognostic relevance of the targets in multiple cancers. We evaluated the anticancer activities against the National Cancer Institute 60 (NCI60) human tumor cell lines and used molecular docking to study the ligand-protein interactions. Finally, we used the DTP-COMPARE algorithm to compare the NSC765598 anticancer fingerprints with NCI standard agents.
We identified mammalian target of rapamycin (mTOR)/epidermal growth factor receptor (EGFR)/inducible nitric oxide synthase (iNOS)/mitogen-activated protein 2 kinase 1 (MAP2K1)/fibroblast growth factor receptor (FGFR)/transforming growth factor-β1 (TGFB1) as potential targets for NSC765598. The targets were enriched in cancer-associated pathways, were overexpressed and were of prognostic relevance in multiple cancers. Among the identified targets, genetic alterations occurred most frequently in EGFR (7%), particularly in glioblastoma, esophageal squamous cell cancer, head and neck squamous cell cancer, and non-small-cell lung cancer, and were associated with poor prognoses and survival of patients, while other targets were less frequently altered. NSC765598 displayed selective antiproliferative and cytotoxic preferences for NSCLC (50% growth inhibition (GI) = 1.12-3.95 µM; total growth inhibition (TGI) = 3.72-16.60 μM), leukemia (GI = 1.20-3.10 µM; TGI = 3.90-12.70 μM), melanoma (GI = 1.45-3.59 µM), and renal cancer (GI = 1.38-3.40 µM; TGI = 4.84-13.70 μM) cell lines, while panels of colon, breast, ovarian, prostate, and central nervous system (CNS) cancer cell lines were less sensitive to NSC765598. Interestingly, NSC765598 docked well into the binding cavity of the targets by conventional H-bonds, van der Waal forces, and a variety of π-interactions, with higher preferences for EGFR (ΔG = -11.0 kcal/mol), NOS2 (ΔG = -11.0 kcal/mol), and mTOR (ΔG = -8.8 kcal/mol). NSC765598 shares similar anti-cancer fingerprints with NCI standard agents displayed acceptable physicochemical values and met the criteria of drug-likeness.
NSC765598 displayed significant anticancer and potential multi-target properties, thus serve as a novel candidate worthy of further preclinical studies.
计算和多组学方法的应用有助于我们理解癌症发生机制和制定治疗策略。NSC765598是水杨酰苯胺的一种新型小分子衍生物。本研究旨在探究NSC765598与其潜在靶点的配体-蛋白质相互作用，并评估其抗癌活性。
我们分别使用多种计算工具和临床数据库来确定NSC765598的潜在药物靶点，并分析这些靶点在多种癌症中的基因特征和预后相关性。我们评估了NSC765598对美国国立癌症研究所60种（NCI60）人类肿瘤细胞系的抗癌活性，并利用分子对接研究配体-蛋白质相互作用。最后，我们使用DTP-COMPARE算法将NSC765598的抗癌指纹图谱与NCI标准药物进行比较。
我们确定哺乳动物雷帕霉素靶蛋白（mTOR）/表皮生长因子受体（EGFR）/诱导型一氧化氮合酶（iNOS）/丝裂原活化蛋白2激酶1（MAP2K1）/成纤维细胞生长因子受体（FGFR）/转化生长因子-β1（TGFB1）为NSC765598的潜在靶点。这些靶点在癌症相关通路中富集，在多种癌症中过表达且与预后相关。在已确定的靶点中，EGFR的基因改变最为频繁（7%），尤其在胶质母细胞瘤、食管鳞状细胞癌、头颈部鳞状细胞癌和非小细胞肺癌中，且与患者预后不良和生存率相关，而其他靶点的改变频率较低。NSC765598对非小细胞肺癌（50%生长抑制（GI）=1.12 - 3.95μM；完全生长抑制（TGI）=3.72 - 16.60μM）、白血病（GI = 1.20 - 3.10μM；TGI = 3.90 - 12.70μM）、黑色素瘤（GI = 1.45 - 3.59μM）和肾癌（GI = 1.38 - 3.40μM；TGI = 4.84 - 13.70μM）细胞系表现出选择性抗增殖和细胞毒性偏好，而结肠、乳腺、卵巢、前列腺和中枢神经系统（CNS）癌细胞系对NSC765598不太敏感。有趣的是，NSC765598通过传统氢键、范德华力和多种π相互作用很好地对接至靶点的结合腔，对EGFR（ΔG = -11.0 kcal/mol）、NOS2（ΔG = -11.0 kcal/mol）和mTOR（ΔG = -8.8 kcal/mol）具有更高的偏好性。NSC765598与NCI标准药物具有相似的抗癌指纹图谱，显示出可接受的理化值并符合类药标准。
NSC765598表现出显著的抗癌活性和潜在的多靶点特性，因此是一个值得进一步进行临床前研究的新型候选药物。
