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In This Issue, Volume 15, Issue 10 本期,第 15 卷第 10 期
IF 3.5 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-10-10 DOI: 10.1021/acsmedchemlett.4c0045310.1021/acsmedchemlett.4c00453
Simone V. Bigi-Botterill*, 
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引用次数: 0
Design, Synthesis, and Biological Evaluation of Selective TBL1X Degraders. 选择性 TBL1X 降解剂的设计、合成和生物学评估。
IF 3.5 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-10-01 eCollection Date: 2024-10-10 DOI: 10.1021/acsmedchemlett.4c00255
Rui Yang, Betsy Pray, Lapo Alinari, Pui Kai Li, Xiaolin Cheng

Transducin β-like protein 1 X-linked (TBL1X) is an essential scaffold protein involved in multiple signaling pathways, such as the Wnt/β-catenin pathway, where it protects β-catenin from ubiquitination and proteasomal degradation. Recent studies, however, suggest that TBL1X might modulate Wnt-regulated genes independently of β-catenin in diffuse large B-cell lymphoma (DLBCL). Here, we developed selective TBL1X degraders against DLBCL using the Proteolysis Targeting Chimeras (PROTACs) strategy as a proof-of-concept. Eight PROTACs showed strong cytotoxic activity. Interestingly, N-linked PROTACs exhibited minimal TBL1X degradation, while most O-linked PROTACs significantly reduced TBL1X levels, suggesting the crucial role of the linker attachment site in successful TBL1X degradation. Our mechanistic study revealed that TBL1X degradation induced by TD11 relied on the formation of the ternary complex and was dependent on the proteasome. The TBL1X degraders developed in this study could be a valuable chemical tool for investigating TBL1X-related pathways.

转导蛋白β样蛋白1 X-连锁(TBL1X)是一种重要的支架蛋白,参与多种信号通路,如Wnt/β-catenin通路,它保护β-catenin免于泛素化和蛋白酶体降解。然而,最近的研究表明,在弥漫大B细胞淋巴瘤(DLBCL)中,TBL1X可能独立于β-catenin而调节Wnt调控基因。在此,我们利用蛋白水解靶向嵌合体(PROTACs)策略开发了针对DLBCL的选择性TBL1X降解剂,作为概念验证。8种PROTACs显示出很强的细胞毒活性。有趣的是,N-连接的PROTACs对TBL1X的降解作用极小,而大多数O-连接的PROTACs则能显著降低TBL1X的水平,这表明连接体的连接位点在成功降解TBL1X中起着至关重要的作用。我们的机理研究发现,TD11诱导的TBL1X降解依赖于三元复合物的形成,并且依赖于蛋白酶体。本研究开发的 TBL1X 降解剂可能是研究 TBL1X 相关途径的一种有价值的化学工具。
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引用次数: 0
Design, Synthesis, and Biological Evaluation of Selective TBL1X Degraders 选择性 TBL1X 降解剂的设计、合成和生物学评估
IF 3.5 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-10-01 DOI: 10.1021/acsmedchemlett.4c0025510.1021/acsmedchemlett.4c00255
Rui Yang, Betsy Pray, Lapo Alinari*, Pui Kai Li* and Xiaolin Cheng*, 

Transducin β-like protein 1 X-linked (TBL1X) is an essential scaffold protein involved in multiple signaling pathways, such as the Wnt/β-catenin pathway, where it protects β-catenin from ubiquitination and proteasomal degradation. Recent studies, however, suggest that TBL1X might modulate Wnt-regulated genes independently of β-catenin in diffuse large B-cell lymphoma (DLBCL). Here, we developed selective TBL1X degraders against DLBCL using the Proteolysis Targeting Chimeras (PROTACs) strategy as a proof-of-concept. Eight PROTACs showed strong cytotoxic activity. Interestingly, N-linked PROTACs exhibited minimal TBL1X degradation, while most O-linked PROTACs significantly reduced TBL1X levels, suggesting the crucial role of the linker attachment site in successful TBL1X degradation. Our mechanistic study revealed that TBL1X degradation induced by TD11 relied on the formation of the ternary complex and was dependent on the proteasome. The TBL1X degraders developed in this study could be a valuable chemical tool for investigating TBL1X-related pathways.

转导蛋白β样蛋白1 X-连锁(TBL1X)是一种重要的支架蛋白,参与多种信号通路,如Wnt/β-catenin通路,它保护β-catenin免于泛素化和蛋白酶体降解。然而,最近的研究表明,在弥漫大B细胞淋巴瘤(DLBCL)中,TBL1X可能独立于β-catenin而调节Wnt调控基因。在此,我们利用蛋白水解靶向嵌合体(PROTACs)策略开发了针对DLBCL的选择性TBL1X降解剂,作为概念验证。8种PROTACs显示出很强的细胞毒活性。有趣的是,N-连接的PROTACs对TBL1X的降解作用极小,而大多数O-连接的PROTACs则能显著降低TBL1X的水平,这表明连接体的连接位点在成功降解TBL1X中起着至关重要的作用。我们的机理研究发现,TD11诱导的TBL1X降解依赖于三元复合物的形成,并且依赖于蛋白酶体。本研究开发的 TBL1X 降解剂可能是研究 TBL1X 相关途径的一种有价值的化学工具。
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引用次数: 0
Lasamide, a Potent Human Carbonic Anhydrase Inhibitor from the Market: Inhibition Profiling and Crystallographic Studies. Lasamide 是一种来自市场的强效人类碳酸酐酶抑制剂:抑制谱分析和晶体学研究。
IF 3.5 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-09-30 eCollection Date: 2024-10-10 DOI: 10.1021/acsmedchemlett.4c00341
Chiara Baroni, Ilaria D'Agostino, Gioele Renzi, Jaydeo T Kilbile, Yasinalli Tamboli, Marta Ferraroni, Simone Carradori, Clemente Capasso, Fabrizio Carta, Claudiu T Supuran

Lasamide is a synthetic precursor and a contaminant of the diuretic Furosemide manufacturing process and represents a highly valuable building block for fragment-based drug discovery approaches. We assessed the ability of Lasamide to inhibit in vitro the human-expressed Carbonic Anhydrases by means of the stopped-flow technique, and we assessed its binding modes within hCAs II and XII-mimic catalytic clefts by X-ray crystallography. Interestingly, an unprecedented crystal form for the hCA IX mimic H-tag is reported and discussed herein.

拉扎米酰胺是一种合成前体,也是利尿剂呋塞米生产过程中的一种污染物,是基于片段的药物发现方法中极具价值的构件。我们通过停流技术评估了 Lasamide 在体外抑制人类表达的碳酸酐酶的能力,并通过 X 射线晶体学评估了它在 hCAs II 和 XII 模拟催化裂隙中的结合模式。有趣的是,本文报告并讨论了一种前所未有的 hCA IX 模拟 H 标记的晶体形式。
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引用次数: 0
Lasamide, a Potent Human Carbonic Anhydrase Inhibitor from the Market: Inhibition Profiling and Crystallographic Studies Lasamide 是一种来自市场的强效人类碳酸酐酶抑制剂:抑制谱分析和晶体学研究
IF 3.5 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-09-30 DOI: 10.1021/acsmedchemlett.4c0034110.1021/acsmedchemlett.4c00341
Chiara Baroni, Ilaria D’Agostino, Gioele Renzi, Jaydeo T. Kilbile, Yasinalli Tamboli, Marta Ferraroni*, Simone Carradori, Clemente Capasso, Fabrizio Carta* and Claudiu T. Supuran, 

Lasamide is a synthetic precursor and a contaminant of the diuretic Furosemide manufacturing process and represents a highly valuable building block for fragment-based drug discovery approaches. We assessed the ability of Lasamide to inhibit in vitro the human-expressed Carbonic Anhydrases by means of the stopped-flow technique, and we assessed its binding modes within hCAs II and XII-mimic catalytic clefts by X-ray crystallography. Interestingly, an unprecedented crystal form for the hCA IX mimic H-tag is reported and discussed herein.

拉扎米酰胺是一种合成前体,也是利尿剂呋塞米生产过程中的一种污染物,是基于片段的药物发现方法中极具价值的构件。我们通过停流技术评估了 Lasamide 在体外抑制人类表达的碳酸酐酶的能力,并通过 X 射线晶体学评估了它在 hCAs II 和 XII 模拟催化裂隙中的结合模式。有趣的是,本文报告并讨论了一种前所未有的 hCA IX 模拟 H 标记的晶体形式。
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引用次数: 0
Exploring the 1-(4-Nitrophenyl)-3-arylprop-2-en-1-one Scaffold for the Selective Inhibition of Monoamine Oxidase B. 探索 1-(4-硝基苯基)-3-芳基丙-2-烯-1-酮支架对单胺氧化酶 B 的选择性抑制作用。
IF 3.5 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-09-27 eCollection Date: 2024-10-10 DOI: 10.1021/acsmedchemlett.4c00246
Rita Meleddu, Antonella Fais, Benedetta Era, Sonia Floris, Simona Distinto, Antonio Lupia, Filippo Cottiglia, Alessia Onali, Erica Sanna, Daniela Secci, Giulia Atzeni, Laura Demuru, Pierluigi Caboni, Donatella Valenti, Elias Maccioni

A small library of 1-(4-nitrophenyl)-3-arylprop-2-en-1-one derivatives was synthesized to identify new human monoamine oxidase B selective inhibitors. Their inhibitory activity toward MAO-A and MAO-B isoforms was evaluated to determine their potency and selectivity. All newly synthesized compounds were nanomolar inhibitors of the B isoform with IC50 concentrations ranging from 120 to 2.2 nM. Conversely, their activity toward the A isozyme was only observed at micromolar concentrations. Our results bear out the hypothesis that the 1,3-diarylpropenone scaffold could represent a valuable starting point for designing efficient and selective MAO-B inhibitors.

为了鉴定新的人类单胺氧化酶 B 选择性抑制剂,我们合成了一个 1-(4-硝基苯基)-3-芳基丙-2-烯-1-酮衍生物的小型文库。评估了它们对 MAO-A 和 MAO-B 同工酶的抑制活性,以确定其效力和选择性。所有新合成的化合物都是 B 型异构体的纳摩尔级抑制剂,IC50 浓度在 120 到 2.2 nM 之间。相反,只有在微摩尔浓度下才能观察到它们对 A 同工酶的活性。我们的研究结果证明了一个假设,即 1,3-二芳基丙烯酮支架可能是设计高效和选择性 MAO-B 抑制剂的重要起点。
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引用次数: 0
Exploring the 1-(4-Nitrophenyl)-3-arylprop-2-en-1-one Scaffold for the Selective Inhibition of Monoamine Oxidase B 探索 1-(4-硝基苯基)-3-芳基丙-2-烯-1-酮支架对单胺氧化酶 B 的选择性抑制作用
IF 3.5 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-09-27 DOI: 10.1021/acsmedchemlett.4c0024610.1021/acsmedchemlett.4c00246
Rita Meleddu, Antonella Fais*, Benedetta Era, Sonia Floris, Simona Distinto, Antonio Lupia, Filippo Cottiglia, Alessia Onali, Erica Sanna, Daniela Secci, Giulia Atzeni, Laura Demuru, Pierluigi Caboni, Donatella Valenti and Elias Maccioni*, 

A small library of 1-(4-nitrophenyl)-3-arylprop-2-en-1-one derivatives was synthesized to identify new human monoamine oxidase B selective inhibitors. Their inhibitory activity toward MAO-A and MAO-B isoforms was evaluated to determine their potency and selectivity. All newly synthesized compounds were nanomolar inhibitors of the B isoform with IC50 concentrations ranging from 120 to 2.2 nM. Conversely, their activity toward the A isozyme was only observed at micromolar concentrations. Our results bear out the hypothesis that the 1,3-diarylpropenone scaffold could represent a valuable starting point for designing efficient and selective MAO-B inhibitors.

为了鉴定新的人类单胺氧化酶 B 选择性抑制剂,我们合成了一个 1-(4-硝基苯基)-3-芳基丙-2-烯-1-酮衍生物的小型文库。评估了它们对 MAO-A 和 MAO-B 同工酶的抑制活性,以确定其效力和选择性。所有新合成的化合物都是 B 型异构体的纳摩尔级抑制剂,IC50 浓度在 120 到 2.2 nM 之间。相反,只有在微摩尔浓度下才能观察到它们对 A 同工酶的活性。我们的研究结果证明了一个假设,即 1,3-二芳基丙烯酮支架可能是设计高效和选择性 MAO-B 抑制剂的重要起点。
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引用次数: 0
Enhanced Plasma Stability and Potency of Aryl/Acyloxy Prodrugs of a BTN3A1 Ligand 增强 BTN3A1 配体芳基/酰氧基原药的血浆稳定性和药效
IF 3.5 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-09-25 DOI: 10.1021/acsmedchemlett.4c0037110.1021/acsmedchemlett.4c00371
Umed Singh, Girija Pawge, Sarita Rani, Chia-Hung Christine Hsiao, David F. Wiemer and Andrew J. Wiemer*, 

While ester-based phosphonate prodrugs excel at delivering payloads into cells, their instability in plasma is a hurdle for their advancement. Here, we synthesized new aryl/acyloxy prodrugs of a phosphonate BTN3A1 ligand. We evaluated their phosphoantigen potency by flow cytometry and ELISA and their plasma and cellular metabolism by LC-MS. These compounds displayed low nanomolar to high picomolar potency. Addition of a p-isopropyl group to the phenyl substituent and use of cyclohexyl or p-methoxybenzyl groups as the acyloxy substituent significantly increased human, but not mouse or rat, plasma stability without negatively impacting potency. Combinations of these prodrug moieties further improved stability, with the best combination achieving a half-life of over 12 h in human plasma, a marked improvement on prior compounds. In contrast, oxane analogs improved water solubility and cellular payload delivery but remained unstable in human plasma. The studies suggest that certain ester-based phosphonate prodrugs quickly deliver active payloads inside cells and show substantial stability in human plasma.

虽然酯类膦酸盐原药在将有效载荷送入细胞方面表现出色,但它们在血浆中的不稳定性却阻碍了它们的发展。在这里,我们合成了膦酸盐 BTN3A1 配体的新芳基/酰氧基原药。我们通过流式细胞仪和酶联免疫吸附试验评估了它们的磷酸抗原效力,并通过 LC-MS 评估了它们的血浆和细胞代谢情况。这些化合物的效力从纳摩尔到皮摩尔不等。在苯基取代基上添加对异丙基,并使用环己基或对甲氧基苄基作为酰氧基取代基,可显著提高人血浆的稳定性,但不会影响小鼠或大鼠的药效。这些原药分子的组合进一步提高了稳定性,最佳组合在人血浆中的半衰期超过 12 小时,明显优于以前的化合物。相比之下,氧烷类似物提高了水溶性和细胞有效载荷的输送,但在人血浆中仍然不稳定。这些研究表明,某些酯类膦酸盐原药能在细胞内快速递送活性有效载荷,并在人血浆中表现出极高的稳定性。
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引用次数: 0
Enhanced Plasma Stability and Potency of Aryl/Acyloxy Prodrugs of a BTN3A1 Ligand. 增强 BTN3A1 配体芳基/酰氧基原药的血浆稳定性和效力
IF 3.5 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-09-25 eCollection Date: 2024-10-10 DOI: 10.1021/acsmedchemlett.4c00371
Umed Singh, Girija Pawge, Sarita Rani, Chia-Hung Christine Hsiao, David F Wiemer, Andrew J Wiemer

While ester-based phosphonate prodrugs excel at delivering payloads into cells, their instability in plasma is a hurdle for their advancement. Here, we synthesized new aryl/acyloxy prodrugs of a phosphonate BTN3A1 ligand. We evaluated their phosphoantigen potency by flow cytometry and ELISA and their plasma and cellular metabolism by LC-MS. These compounds displayed low nanomolar to high picomolar potency. Addition of a p-isopropyl group to the phenyl substituent and use of cyclohexyl or p-methoxybenzyl groups as the acyloxy substituent significantly increased human, but not mouse or rat, plasma stability without negatively impacting potency. Combinations of these prodrug moieties further improved stability, with the best combination achieving a half-life of over 12 h in human plasma, a marked improvement on prior compounds. In contrast, oxane analogs improved water solubility and cellular payload delivery but remained unstable in human plasma. The studies suggest that certain ester-based phosphonate prodrugs quickly deliver active payloads inside cells and show substantial stability in human plasma.

虽然酯类膦酸盐原药在将有效载荷送入细胞方面表现出色,但它们在血浆中的不稳定性却阻碍了它们的发展。在这里,我们合成了膦酸盐 BTN3A1 配体的新芳基/酰氧基原药。我们通过流式细胞仪和酶联免疫吸附试验评估了它们的磷酸抗原效力,并通过 LC-MS 评估了它们的血浆和细胞代谢情况。这些化合物的效力从纳摩尔到皮摩尔不等。在苯基取代基上添加对异丙基,并使用环己基或对甲氧基苄基作为酰氧基取代基,可显著提高人血浆的稳定性,但不会影响小鼠或大鼠的药效。这些原药分子的组合进一步提高了稳定性,最佳组合在人血浆中的半衰期超过 12 小时,明显优于以前的化合物。相比之下,氧烷类似物提高了水溶性和细胞有效载荷的输送,但在人血浆中仍然不稳定。这些研究表明,某些酯类膦酸盐原药能在细胞内快速递送活性有效载荷,并在人血浆中表现出极高的稳定性。
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引用次数: 0
Design, Biological Characterization, and Discovery of Novel Cyclohexenyl Derivatives as Kinesin KIF18A Inhibitors for the Treatment of Ovarian Cancer 作为治疗卵巢癌的驱动蛋白 KIF18A 抑制剂的新型环己烯基衍生物的设计、生物学特性和发现
IF 4.2 3区 医学 Q2 CHEMISTRY, MEDICINAL Pub Date : 2024-09-17 DOI: 10.1021/acsmedchemlett.4c00383
Chen Zhang, Peng Tu, Xiangyu Jia, Yuanfeng Xia, Biao Lu, Fanglong Yang, Siqin Wang, Lei Jin
A novel class of kinesin KIF18A inhibitors were discovered through modification of the clinical compound AMG650. Structure–activity relationship (SAR) study led to the discovery of compound 16 with an alkenyl motif, a highly potent KIF18A inhibitor, which displayed a favorable pharmacological profile and excellent efficacy in a mouse model of an OVCAR-3 xenograft tumor. Oral administration of 16 can induce a dose-dependent antitumor efficacy in the OVCAR-3 model without significant reduction in body weight. Compound 16 showed potential as a candidate for the clinical treatment of ovarian cancer.
通过对临床化合物 AMG650 进行改造,发现了一类新型驱动蛋白 KIF18A 抑制剂。通过结构-活性关系(SAR)研究,发现了具有烯基基团的化合物 16,它是一种高效的 KIF18A 抑制剂,在小鼠 OVCAR-3 异种移植瘤模型中显示出良好的药理特征和卓越的疗效。口服 16 可在 OVCAR-3 模型中产生剂量依赖性抗肿瘤疗效,且体重不会明显减轻。化合物 16 具有临床治疗卵巢癌的潜力。
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引用次数: 0
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ACS Medicinal Chemistry Letters
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