Department of Biotechnology, Lady Doak College, Madurai Kamaraj University, Thallakulam, Madurai 625002, India.
Molecular Signaling Group, Faculty of Medicine and Health Technology, Tampere University and BioMediTech, P.O. Box 553, 33101 Tampere, Finland.
Int J Mol Sci. 2023 Jul 31;24(15):12276. doi: 10.3390/ijms241512276.
The tropomyosin receptor kinase A (TrkA) family of receptor tyrosine kinases (RTKs) emerge as a potential target for glioblastoma (GBM) treatment. Benzenesulfonamide analogs were identified as kinase inhibitors possessing promising anticancer properties. In the present work, four known and two novel benzenesulfonamide derivatives were synthesized, and their inhibitory activities in TrkA overexpressing cells, U87 and MEF cells were investigated. The cytotoxic effect of benzenesulfonamide derivatives and cisplatin was determined using trypan blue exclusion assays. The mode of interaction of benzenesulfonamides with TrkA was predicted by docking and structural analysis. ADMET profiling was also performed for all compounds to calculate the drug likeness property. Appropriate QSAR models were developed for studying structure-activity relationships. Compound 4-[2-(4,4-dimethyl-2,6-dioxocyclohexylidene)hydrazinyl]--(5-methyl-1,3,4-thiadiazol-2-yl)benzenesulfon-amide (AL106) and 4-[2-(1,3-dioxo-1,3-dihydro-2-inden-2-ylidene)hydrazinyl]--(5-methyl-1,3,4-thiadiazol-2-yl)benzenesulfonamide (AL107) showed acceptable binding energies with the active sites for human nerve growth factor receptor, TrkA. Here, AL106 was identified as a potential anti-GBM compound, with an IC value of 58.6 µM with a less toxic effect in non-cancerous cells than the known chemotherapeutic agent, cisplatin. In silico analysis indicated that AL106 formed prominent stabilizing hydrophobic interactions with Tyr359, Ser371, Ile374 and charged interactions with Gln369 of TrkA. Furthermore, in silico analysis of all benzenesulfonamide derivatives revealed that AL106 has good pharmacokinetics properties, drug likeness and toxicity profiles, suggesting the compound may be suitable for clinical trial. Thus, benzenesulfonamide analog, AL106 could potentially induce GBM cell death through its interaction with TrkA and might be an attractive strategy for developing a drug targeted therapy to treat glioblastoma.
原肌球蛋白受体激酶 A（TrkA）家族的受体酪氨酸激酶（RTKs）成为胶质母细胞瘤（GBM）治疗的潜在靶点。苯磺酰胺类似物被鉴定为具有有前途的抗癌特性的激酶抑制剂。在本工作中，合成了四个已知和两个新型苯磺酰胺衍生物，并研究了它们在高表达 TrkA 的细胞 U87 和 MEF 中的抑制活性。使用台盼蓝排除试验测定苯磺酰胺衍生物和顺铂的细胞毒性作用。通过对接和结构分析预测苯磺酰胺与 TrkA 的相互作用模式。还对所有化合物进行了 ADMET 分析以计算药物相似性。为了研究构效关系，还开发了适当的 QSAR 模型。化合物 4-[2-(4,4-二甲基-2,6-二氧环己基)肼基]-(5-甲基-1,3,4-噻二唑-2-基)苯磺酰胺（AL106）和 4-[2-(1,3-二氧代-1,3-二氢-2-茚基)肼基]-(5-甲基-1,3,4-噻二唑-2-基)苯磺酰胺（AL107）与人类神经生长因子受体 TrkA 的活性位点显示出可接受的结合能。在这里，AL106 被鉴定为具有潜力的抗 GBM 化合物，其 IC 值为 58.6 µM，在非癌细胞中的毒性作用小于已知的化疗药物顺铂。计算机分析表明，AL106 与 TrkA 的 Tyr359、Ser371、Ile374 形成了突出的稳定疏水性相互作用，并与 Gln369 形成了带电相互作用。此外，对所有苯磺酰胺衍生物的计算机分析表明，AL106 具有良好的药代动力学特性、药物相似性和毒性特征，表明该化合物可能适合临床试验。因此，苯磺酰胺类似物 AL106 可能通过与 TrkA 的相互作用诱导 GBM 细胞死亡，并且可能是开发针对胶质母细胞瘤的靶向治疗药物的有吸引力的策略。
