Targeting WWPI HECT Domain by Small Inhibitors for Restoring PTEN Tumor Suppressive Role in Glioblastoma Therapy.

IF 3 4区 医学 Q3 CHEMISTRY, MEDICINAL
Atta Ullah, Majid Khan, Sadeeq Ur Rahman, Usama Qayum, Najeeb Ur Rehman, Magda H Abdellattif, Magdy Mohamed Ahmed Elshamy, Alaa Abu Alnjaa, Sobia Ahsan Halim, Ajmal Khan, Ahmed Al-Harrasi
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引用次数: 0

Abstract

Introduction: PTEN (Phosphatase and tensin homolog) is a valuable regulator of the PI3K-AKT and mTOR pathways and is frequently mutated in cancer-like glioblastoma. The WWPI HECT domain has a group of enzymes called E3 ligases that ubiquitinate and inactivate PTEN by binding to it, which ultimately inhibits its lipid phosphatase function and promotes nuclear delocalization. This investigation seeks to restore the PTEN tumor suppressive activity by inhibiting the WWPI HECT domain in-silico.

Methods: We virtually screened a library of ~960 compounds in the active pocket of the human WWPI HECT domain, and fifteen compounds were chosen based on their favorable binding affinities and highly negative docking scores.

Results: Among those hits, five compounds, C5, C6, C8, C9 and C11, properly fit the standard with favorable pharmacokinetic and drug-like quality. Their capacity to suppress cell propagation was evaluated in the U87 glioma cell line. The compounds (C5, C6, C8, C9 and C11) exhibited significant anti-proliferative capability with IC50 values of 6.98 ± 0.14 μM, 14.58 ± 1.49 μM, 11.12 ± 0.73 μM, 13.85 ± 1.63 μM and 18 ± 1.23 μM, respectively.

Discussion: Strong inhibitory action against glioma cells was shown by the discovered compounds, especially C5 and C8, suggesting that they may be able to restore PTEN tumor suppressive capabilities. A potential therapeutic intervention mechanism for glioblastoma is suggested by their interaction with the WWPI HECT domain.

Conclusion: This study has discovered novel inhibitors against the WWPI HECT domain, and a treatment option for glioblastoma.

利用小抑制剂靶向WWPI HECT结构域恢复PTEN在胶质母细胞瘤治疗中的抑瘤作用。
简介:PTEN(磷酸酶和紧张素同源物)是PI3K-AKT和mTOR通路的重要调节因子,在癌样胶质母细胞瘤中经常发生突变。WWPI HECT结构域有一组称为E3连接酶的酶,通过与PTEN结合使其泛素化并失活,最终抑制其脂质磷酸酶功能并促进核离域。本研究旨在通过抑制WWPI HECT结构域来恢复PTEN的肿瘤抑制活性。方法:我们对人类WWPI HECT结构域活性口袋中的约960个化合物进行了虚拟筛选,并根据其良好的结合亲和力和高负对接评分选择了15个化合物。结果:C5、C6、C8、C9、C11 5个化合物符合标准,具有良好的药动学和类药质量。在U87胶质瘤细胞系中评估了它们抑制细胞繁殖的能力。化合物C5、C6、C8、C9和C11的IC50值分别为6.98±0.14 μM、14.58±1.49 μM、11.12±0.73 μM、13.85±1.63 μM和18±1.23 μM。讨论:发现的化合物对胶质瘤细胞有较强的抑制作用,特别是C5和C8,提示它们可能能够恢复PTEN的抑瘤能力。胶质母细胞瘤的潜在治疗干预机制是通过它们与WWPI HECT结构域的相互作用提出的。结论:本研究发现了新的抑制WWPI HECT结构域的抑制剂,为胶质母细胞瘤的治疗提供了新的选择。
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来源期刊
Anti-cancer agents in medicinal chemistry
Anti-cancer agents in medicinal chemistry ONCOLOGY-CHEMISTRY, MEDICINAL
CiteScore
5.10
自引率
3.60%
发文量
323
审稿时长
4-8 weeks
期刊介绍: Formerly: Current Medicinal Chemistry - Anti-Cancer Agents. Anti-Cancer Agents in Medicinal Chemistry aims to cover all the latest and outstanding developments in medicinal chemistry and rational drug design for the discovery of anti-cancer agents. Each issue contains a series of timely in-depth reviews and guest edited issues written by leaders in the field covering a range of current topics in cancer medicinal chemistry. The journal only considers high quality research papers for publication. Anti-Cancer Agents in Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments in cancer drug discovery.
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