Noncovalent CDK12/13 dual inhibitors-based PROTACs degrade CDK12-Cyclin K complex and induce synthetic lethality with PARP inhibitor was written by Niu, Tian;Li, Kailin;Jiang, Li;Zhou, Zhesheng;Hong, Ju;Chen, Xuankun;Dong, Xiaowu;He, Qiaojun;Cao, Ji;Yang, Bo;Zhu, Cheng-Liang. And the article was included in European Journal of Medicinal Chemistry in 2022.Name: 2-(2-Methoxyethoxy)ethanol This article mentions the following:
Cyclin-dependent kinase 12 (CDK12) plays a crucial role in DNA-damage response gene transcription and has recently been validated as a promising target in cancer therapy. However, existing CDK12 inhibitors potently inhibit its closest isoform CDK13, which could cause potential toxicity. Therefore, the development of CDK12 inhibitors with isoform-selectivity against CDK13 continues to be a challenge. By taking advantage of the emerging PROteolysis-TArgeting Chimeras (PROTACs) approach, we have synthesized a potent PROTAC degrader PP-C8 based on the noncovalent dual inhibitors of CDK12/13 and demonstrated its specificity for CDK12 over CDK13. Notably, PP-C8 induces profound degradation of cyclin K simultaneously and downregulates the mRNA level of DNA-damage response genes. Global proteomics profiling revealed PP-C8 is highly selective toward CDK12-cyclin K complex. Importantly, PP-C8 demonstrates profound synergistic antiproliferative effects with PARP inhibitor in triple-neg. breast cancer (TNBC). The potent and selective CDK12 PROTAC degrader developed in this study could potentially be used to treat CDK12-dependent cancers as combination therapy. In the experiment, the researchers used many compounds, for example, 2-(2-Methoxyethoxy)ethanol (cas: 111-77-3Name: 2-(2-Methoxyethoxy)ethanol).
2-(2-Methoxyethoxy)ethanol (cas: 111-77-3) belongs to ethers. Of all the functional groups, ethers are the least reactive ones. Ether bonds are quite stable towards bases, oxidizing agents and reducing agents. But on the other hand, ethers undergo cleavage by reaction with acids. Ethers feature bent C–O–C linkages. In dimethyl ether, the bond angle is 111° and C–O distances are 141 pm. The barrier to rotation about the C–O bonds is low. The bonding of oxygen in ethers, alcohols, and water is similar. In the language of valence bond theory, the hybridization at oxygen is sp3.Name: 2-(2-Methoxyethoxy)ethanol
Referemce:
Ether – Wikipedia,
Ether | (C2H5)2O – PubChem