在过去的二十年里,随着IMiD和indisulam等MG降解剂的出现,分子胶(MGs)逐渐引起了制药界的关注。这些分子通过促进靶蛋白和E3连接酶之间的相互作用来降解靶蛋白。此外,MGs作为化学诱导剂,促进同源蛋白和异源蛋白的二聚化形成三元复合物,...在过去的二十年里,随着IMiD和indisulam等MG降解剂的出现,分子胶(MGs)逐渐引起了制药界的关注。这些分子通过促进靶蛋白和E3连接酶之间的相互作用来降解靶蛋白。此外,MGs作为化学诱导剂,促进同源蛋白和异源蛋白的二聚化形成三元复合物,在调节生物活性方面具有很大的前景。本文重点介绍MGs在药物开发领域的应用,包括蛋白质–蛋白质相互作用(PPI)稳定性和蛋白质降解。我们深入分析了各种MGs的结构以及MGs与各种生物活性分子之间的相互作用,从而为PPI稳定剂和新型降解剂的开发提供了新的视角。Over the past two decades, molecular glues (MGs) have gradually attracted the attention of the pharmaceutical community with the advent of MG degraders such as IMiDs and indisulam. Such molecules degrade the target protein by promoting the interaction between the target protein and E3 ligase. In addition, as a chemical inducer, MGs promote the dimerization of homologous proteins and heterologous proteins to form ternary complexes, which have great prospects in regulating biological activities. This review focuses on the application of MGs in the field of drug development including protein-protein interaction (PPI) stability and protein degradation. We thoroughly analyze the structure of various MGs and the interactions between MGs and various biologically active molecules, thus providing new perspectives for the development of PPI stabilizers and new degraders.展开更多
醛酮还原酶家族1成员C3 (AKR1C3),也被称为5型17β羟基类固醇脱氢酶(17β-HSD5)或前列腺素F (PGF)合成酶,在雄激素生物合成中起关键作用。它催化弱雄激素、雌酮(弱雌激素)和PGD2分别转化为强雄激素(睾酮和5α-二氢睾酮)、17β-雌二醇(...醛酮还原酶家族1成员C3 (AKR1C3),也被称为5型17β羟基类固醇脱氢酶(17β-HSD5)或前列腺素F (PGF)合成酶,在雄激素生物合成中起关键作用。它催化弱雄激素、雌酮(弱雌激素)和PGD2分别转化为强雄激素(睾酮和5α-二氢睾酮)、17β-雌二醇(强雌激素)和11β-PGF2α。AKR1C3水平升高激活雄激素受体(AR) 8信号通路,促进肿瘤复发和对癌症治疗产生耐药性。AKR1C3的过表达作为一种致癌因子,促进癌细胞的增殖、侵袭和转移,并与癌症患者的不良预后和总生存期相关。抑制AKR1C3已被证明在抑制肿瘤进展和克服治疗耐药性方面具有强大的功效。因此,AKR1C3抑制剂的开发和设计引起了研究人员越来越多的兴趣,近年来取得了重大进展。本文简要介绍了AKR1C3的生理和病理功能,并对近年来选择性AKR1C3抑制剂的研究进展进行了综述。我们的目的是为未来的药物发现和潜在的治疗前景提供参考,新的、有效的、选择性的AKR1C3抑制剂。Aldo-Keto Reductase Family 1 Member C3 (AKR1C3), also known as type 5 17β-hydroxysteroid dehydrogenase (17β-HSD5) or prostaglandin F (PGF) synthase, functions as a pivotal enzyme in androgen biosynthesis. It catalyzes the conversion of weak androgens, estrone (a weak estrogen), and PGD2 into potent androgens (testosterone and 5α-dihydrotestosterone), 17β-estradiol (a potent estrogen), and 11β-PGF2α, respectively. Elevated levels of AKR1C3 activate androgen receptor (AR) signaling pathway, contributing to tumor recurrence and imparting resistance to cancer therapies. The overexpression of AKR1C3 serves as an oncogenic factor, promoting carcinoma cell proliferation, invasion, and metastasis, and is correlated with unfavorable prognosis and overall survival in carcinoma patients. Inhibiting AKR1C3 has demonstrated potent efficacy in suppressing tumor progression and overcoming treatment resistance. As a result, the development and design of AKR1C3 inhibitors have garnered increasing interest among researchers, with significant progress witnessed in recent years. Here, we briefly review the physiological and pathological function of AKR1C3 and then summarize the recent development of selective AKR1C3 inhibitors. We aim to provide a reference for future drug discovery and potential therapeutic perspectives on novel, potent, selective AKR1C3 inhibitors.展开更多
文摘在过去的二十年里,随着IMiD和indisulam等MG降解剂的出现,分子胶(MGs)逐渐引起了制药界的关注。这些分子通过促进靶蛋白和E3连接酶之间的相互作用来降解靶蛋白。此外,MGs作为化学诱导剂,促进同源蛋白和异源蛋白的二聚化形成三元复合物,在调节生物活性方面具有很大的前景。本文重点介绍MGs在药物开发领域的应用,包括蛋白质–蛋白质相互作用(PPI)稳定性和蛋白质降解。我们深入分析了各种MGs的结构以及MGs与各种生物活性分子之间的相互作用,从而为PPI稳定剂和新型降解剂的开发提供了新的视角。Over the past two decades, molecular glues (MGs) have gradually attracted the attention of the pharmaceutical community with the advent of MG degraders such as IMiDs and indisulam. Such molecules degrade the target protein by promoting the interaction between the target protein and E3 ligase. In addition, as a chemical inducer, MGs promote the dimerization of homologous proteins and heterologous proteins to form ternary complexes, which have great prospects in regulating biological activities. This review focuses on the application of MGs in the field of drug development including protein-protein interaction (PPI) stability and protein degradation. We thoroughly analyze the structure of various MGs and the interactions between MGs and various biologically active molecules, thus providing new perspectives for the development of PPI stabilizers and new degraders.
文摘醛酮还原酶家族1成员C3 (AKR1C3),也被称为5型17β羟基类固醇脱氢酶(17β-HSD5)或前列腺素F (PGF)合成酶,在雄激素生物合成中起关键作用。它催化弱雄激素、雌酮(弱雌激素)和PGD2分别转化为强雄激素(睾酮和5α-二氢睾酮)、17β-雌二醇(强雌激素)和11β-PGF2α。AKR1C3水平升高激活雄激素受体(AR) 8信号通路,促进肿瘤复发和对癌症治疗产生耐药性。AKR1C3的过表达作为一种致癌因子,促进癌细胞的增殖、侵袭和转移,并与癌症患者的不良预后和总生存期相关。抑制AKR1C3已被证明在抑制肿瘤进展和克服治疗耐药性方面具有强大的功效。因此,AKR1C3抑制剂的开发和设计引起了研究人员越来越多的兴趣,近年来取得了重大进展。本文简要介绍了AKR1C3的生理和病理功能,并对近年来选择性AKR1C3抑制剂的研究进展进行了综述。我们的目的是为未来的药物发现和潜在的治疗前景提供参考,新的、有效的、选择性的AKR1C3抑制剂。Aldo-Keto Reductase Family 1 Member C3 (AKR1C3), also known as type 5 17β-hydroxysteroid dehydrogenase (17β-HSD5) or prostaglandin F (PGF) synthase, functions as a pivotal enzyme in androgen biosynthesis. It catalyzes the conversion of weak androgens, estrone (a weak estrogen), and PGD2 into potent androgens (testosterone and 5α-dihydrotestosterone), 17β-estradiol (a potent estrogen), and 11β-PGF2α, respectively. Elevated levels of AKR1C3 activate androgen receptor (AR) signaling pathway, contributing to tumor recurrence and imparting resistance to cancer therapies. The overexpression of AKR1C3 serves as an oncogenic factor, promoting carcinoma cell proliferation, invasion, and metastasis, and is correlated with unfavorable prognosis and overall survival in carcinoma patients. Inhibiting AKR1C3 has demonstrated potent efficacy in suppressing tumor progression and overcoming treatment resistance. As a result, the development and design of AKR1C3 inhibitors have garnered increasing interest among researchers, with significant progress witnessed in recent years. Here, we briefly review the physiological and pathological function of AKR1C3 and then summarize the recent development of selective AKR1C3 inhibitors. We aim to provide a reference for future drug discovery and potential therapeutic perspectives on novel, potent, selective AKR1C3 inhibitors.
