Direct-to-Biology Accelerates PROTAC Synthesis and the Evaluation of Linker Effects on Permeability and Degradation

A platform to accelerate optimization of proteolysis targeting chimeras (PROTACs) has been developed using a direct-to-biology (D2B) approach with a focus on linker effects. A large number of linker analogs—with varying length, polarity, and rigidity—were rapidly prepared and characterized in four cell-based assays by streamlining time-consuming steps in synthesis and purification. The expansive dataset informs on linker structure–activity relationships (SAR) for in-cell E3 ligase target engagement, degradation, permeability, and cell toxicity. Unexpected aspects of linker SAR was discovered, consistent with literature reports on “linkerology”, and the method dramatically speeds up empirical optimization. Physicochemical property trends emerged, and the platform has the potential to rapidly expand training sets for more complex prediction models. In-depth validation studies were carried out and confirm the D2B platform is a valuable tool to accelerate PROTAC design–make–test cycles.     

Targeting histone deacetylases for cancer therapy: Trends and challenges

Dysregulation of histone deacetylases(HDACs) is closely related to tumor development and progression. As promising anticancer targets, HDACs have gained a great deal of research interests and two decades of effort has led to the approval of five HDAC inhibitors(HDACis). However, currently traditional HDACis, although effective in approved indications, exhibit severe off-target toxicities and low sensitivities against solid tumors, which have urged the development of next-generation of HDACi. Thi...     

载PROTAC分子白蛋白纳米粒的构建及对胶质瘤细胞NAD+代谢的抑制

目的 制备载蛋白降解靶向嵌合体（PROTAC）分子的白蛋白纳米粒并优化处方,考察纳米粒对胶质瘤细胞增殖活性及烟酰胺腺嘌呤二核苷酸（NAD⁺）代谢的抑制。方法 以热驱动法制备载NPT-B2的白蛋白纳米粒并表征,建立NPT-B2的高效液相色谱（HPLC）检测方法,以CCK8法和蛋白免疫印迹法分别考察NPT-B2和白蛋白纳米粒（B2-BSA-NPs）对胶质瘤细胞的增值活性抑制作用,及肿瘤细胞限速酶-烟酰胺磷酸核糖转移酶（NAMPT）的降解。结果 HPLC方法线性良好,精密度、回收率符合测定要求。纳米粒粒径为55.48 nm、电位-12.9 mV,包封率94.74%,载药量8.61%。NPT-B2对胶质瘤细胞的IC₅₀为61.16 nmol/L,同时具有NAMPT降解作用。B2-BSA-NPs对胶质瘤细胞的IC₅₀为41.21 nmol/L,对NAMPT具有非常显著降解效果。结论 构建了载PROTAC分子的白蛋白纳米粒,优化处方提高药物包封率,改善PROTAC分子水溶性差的问题,纳米粒对胶质瘤细胞增殖活性及NAD⁺能量代谢有显著抑制作用。     

Rational Control of Molecular Properties Is Mandatory to Exploit the Potential of PROTACs as Oral Drugs

To obtain new oral drugs in the beyond rule of five space, PROTACs among others, molecular properties should be optimized in early drug discovery. Degraders call for design strategies which focus on intramolecular interaction and chameleonicity. In parallel, tailored revalidation of permeability assessment and prediction methods becomes fundamental in this innovative chemical space.     

The rise and rise of protein degradation: Opportunities and challenges ahead

The transformational mechanism of action underpinning targeted protein degradation strategies, including proteolysis-targeting chimeras (PROTACs), gives potential for potent in vivo pharmacology and has allowed projects to move rapidly to the clinic. Despite this remarkable progress, there remain many opportunities to improve current, first-generation approaches even further. Our expanding knowledge will allow discovery of new degrading mechanisms with potential to address several limitations of current approaches, including improving scope and efficiency of degradation, improving drug-like properties of degraders, and reducing potential for the emergence of acquired resistance. Here, we discuss potential routes to realize these advances to expand TPD utility even further.     

蛋白降解靶向嵌合体药物(PROTAC)的非临床评价策略分析

蛋白降解靶向嵌合体(PROTAC)将靶向蛋白募集到E3泛素连接酶进行泛素化标记,然后通过泛素-蛋白酶体途径将其降解,从而将过表达和突变的致病蛋白清除。本文基于已有的文献报道,总结PROTAC药物研发进展,针对其存在的相对分子质量较大、生物利用度低、稳定性和血管穿透能力差等问题提出应对策略,并从药理药效、代谢和安全性评价等方面对该类药物的非临床评价研究需要考虑的问题进行分析,为制定PROTAC药物非临床评价研究方案提供参考。     

蛋白降解靶向嵌合体在小分子药物研发中的机遇与挑战

蛋白降解靶向嵌合体（PROTAC）技术是一种通过泛素-蛋白酶体途径化学诱导靶蛋白降解的新兴策略。PROTAC是由靶蛋白配体和E3泛素连接酶配体通过适当的连接链连接而成的双功能分子,能够同时招募靶蛋白和E3泛素连接酶,从而诱导靶蛋白泛素化降解,具有广泛的应用前景和发展空间。主要简述小分子PROTAC的降解机制、发展历程,以及在药物研发中面临的机遇与挑战。