Graduate School of Pharmaceutical Sciences, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan.
School of Pharmacy and Pharmaceutical Sciences, Hoshi University, 2-4-41 Ebara, Shinagawa-ku, Tokyo 142-8501, Japan.
Bioconjug Chem. 2022 Jan 19;33(1):142-151. doi: 10.1021/acs.bioconjchem.1c00490. Epub 2021 Dec 8.
Trivalent PROTACs having a functionalization site with controlled orientation were designed, synthesized, and evaluated. Based on the X-ray structure of BRD protein degrader MZ1 () in complex with human VHL and BRD4, we expected that the 1,2-disubstituted ethyl group near the JQ-1 moiety in MZ1 () could be replaced by a planar benzene tether as a platform for further functionalization. To test this hypothesis, we first designed six divalent MZ1 derivatives, and , by combining three variations of substitution patterns on the benzene ring (1,2-, 1,3-, and 1,4-substitution) and two variations in the number of ethylene glycol units (2 or 1). We then tested the synthesized compounds for the BRD4 degradation activity of each. As expected, we found that 1,2D-EG2-MZ1 (), an MZ1 derivative with 1,2-disubstituted benzene possessing two ethylene glycol units, had an activity profile similar to that of MZ1 (). Based on the structure of , we then synthesized and evaluated four isomeric trivalent MZ1 derivatives, , having a -butyl ester unit on the benzene ring as a handle for further functionalization. Among the four isomers, 1,2,5T-EG2-MZ1 () retained a level of BRD4 depletion activity similar to that of without inducing a measurable Hook effect, and its BRD4 depletion kinetics was the same as that of MZ1 (). Other isomers were also shown to retain BRD4 depletion activity. Thus, the trivalent PROTACs we synthesized here may serve as efficient platforms for further applications.
三价 PROTACs 具有具有受控取向的功能化位点，我们对其进行了设计、合成和评估。基于 BRD 蛋白降解剂 MZ1（）与人类 VHL 和 BRD4 复合物的 X 射线结构，我们期望 MZ1（）中靠近 JQ-1 部分的 1,2-二取代乙基基团可以被平面苯系物取代，作为进一步功能化的平台。为了验证这一假设，我们首先设计了六个二价 MZ1 衍生物，和，通过结合苯环上三种取代模式（1,2-、1,3-和 1,4-取代）和乙二醇单元数量的两种变化（2 或 1）。然后，我们测试了合成化合物对每种 BRD4 降解活性的影响。正如预期的那样，我们发现 1,2D-EG2-MZ1（），一种具有两个乙二醇单元的 1,2-二取代苯的 MZ1 衍生物，具有与 MZ1（）相似的活性谱。基于的结构，我们随后合成并评估了四个具有苯环上作为进一步功能化手柄的 -丁酯单元的同分异构三价 MZ1 衍生物，，。在这四个异构体中，1,2,5T-EG2-MZ1（）保留了与无诱导可测量 Hook 效应的相似的 BRD4 耗竭活性，并且其 BRD4 耗竭动力学与 MZ1（）相同。其他异构体也被证明保留了 BRD4 耗竭活性。因此，我们在这里合成的三价 PROTACs 可能成为进一步应用的有效平台。
