1061605-21-7Relevant articles and documents
Selective degradation-inducing probes for studying cereblon (CRBN) biology
Bushman, Jonathan W.,Du, Guangyan,Fischer, Eric S.,Gray, Nathanael S.,He, Zhixiang,Powell, Chelsea E.,Zhang, Tinghu
, p. 1381 - 1390 (2021)
Targeted protein degradation represents a rapidly growing area in drug discovery and development. Moreover, small molecules that induce the targeted degradation of a given protein also represent an important addition to the chemical probes toolbox as these compounds can achieve selective protein knockdown, thus providing an approach that is orthogonal to genetic knockdowns. In order to develop degradation-inducing chemical probes for studying cereblon (CRBN) biology, we generated six CRBN-CRBN (homo-PROTAC) degraders and six CRBN-VHL (hetero-PROTAC) degraders. From these compounds we identified two potent and selective CRBN degraders (ZXH-4-130 and ZXH-4-137), both of which are CRBN-VHL compounds. We characterized these lead degraders by quantitative proteomics in five cell lines (MM1.S, Kelly, SK-N-DZ, HEK293T, and MOLT-4) and observed high selectivity for CRBN in all cell lines. Furthermore, we directly compared our compounds to current lead CRBN degraders and demonstrated how these probes can be used as chemical knockdown reagents for studying CRBN-dependent processes. Overall, our work provides a roadmap for thorough degrader characterization by combination western and proteomic analysis, as illustrated by the identification of ZXH-4-130 and ZXH-4-137 as CRBN-knockdown tool compounds suitable for cell-based studies.
Practical synthesis of a phthalimide-based Cereblon ligand to enable PROTAC development
Lohbeck, Jasmin,Miller, Aubry K.
, p. 5260 - 5262 (2016)
The use of small molecules to regulate cellular levels of specific proteins is poised to become a powerful technique in the coming years. Critical to the success of any project utilizing such an approach will be the ability to synthesize libraries of candidate small molecules for testing in cellular systems. Herein, we describe a practical synthesis of a phthalimide-based scaffold, which can be easily diversified to make Cereblon-targeting PROTACs. We demonstrate the effectiveness of this approach by synthesizing a ‘PROTAC toolbox’ of four amines which can be coupled to inhibitors in a straightforward manner.
PROTACs suppression of GSK-3β, a crucial kinase in neurodegenerative diseases
Jiang, Xueyang,Zhou, Junting,Wang, Yang,Liu, Xin,Xu, Kaiying,Xu, Jian,Feng, Feng,Sun, Haopeng
, (2021)
Glycogen synthase kinase 3β (GSK-3β) is involved in a variety of diseases such as neurodegenerative diseases, bipolar disorder, and diabetes. In this study, a series of heterobifunctional small molecule proteolysis targeting chimera (PROTAC) were designed and synthesized based on E3 ubiquitin ligase cereblon (CRBN). Most of PROTACs displayed good inhibitory activity, with the IC50 values at the double-digits nanomolar levels and moderate protein degradation ability against GSK-3β. Western-blot data showed compound PG21 can effectively degrade GSK-3β in a dose-dependent manner, which can induce 44.2% protein degradation at 2.8 μM. Further pharmacological experiments revealed that the ability of PG21 to degrade GSK-3β is mediated by the ubiquitin-proteasome system (UPS). In addition, PG21 protects against glutamate-induced cell death in HT-22 cells. As the first PROTAC example to degrade GSK-3β protein, the present study has provided potential candidates for further investigation in the biological function of GSK-3β protein and its association with diseases.
Discovery of a PROTAC targeting ALK with in vivo activity
Yan, Guoyi,Zhong, Xinxin,Yue, Lin,Pu, Chunlan,Shan, Huifang,Lan, Suke,Zhou, Meng,Hou, Xueyan,Yang, Jie,Li, Rui
, (2021)
Anaplastic lymphoma kinase (ALK) was involved in the development of various cancer types. Although several ALK inhibitors have been advanced to clinical trials, the emergence of drug resistance has limited the clinical application of them. To overcome the drug resistance, proteolysis targeting chimeras (PROTACs) could be an alternative strategy. In this study, a series of ALK degraders were designed and synthesized. The degraders were developed through the conjugation of LDK378 and CRBN E3 ubiquitin ligase ligands. Among all the molecules, compound B3 showed potent selective inhibitory activity to ALK and can decrease the cellular levels of ALK fusion proteins in a concentration- and time-dependent manner in H3122 cell line. Meanwhile, B3 showed improved anticancer activity in vitro comparing with LDK378 and the antiproliferative activity to xenograft tumor model was acceptable. All the results demonstrated that ALK degrader B3 with in vitro and in vivo anti-cancer activities was valuable for further investigation.
Homolog-Selective Degradation as a Strategy to Probe the Function of CDK6 in AML
Brand, Matthias,Jiang, Baishan,Bauer, Sophie,Donovan, Katherine A.,Liang, Yanke,Wang, Eric S.,Nowak, Rados?aw P.,Yuan, Jingting C.,Zhang, Tinghu,Kwiatkowski, Nicholas,Müller, André C.,Fischer, Eric S.,Gray, Nathanael S.,Winter, Georg E.
, p. 300 - 9,306 (2019)
The design of selective small molecules is often stymied by similar ligand binding pockets. Here, we report BSJ-03-123, a phthalimide-based degrader that exploits protein-interface determinants to achieve proteome-wide selectivity for the degradation of cyclin-dependent kinase 6 (CDK6). Pharmacologic CDK6 degradation targets a selective dependency of acute myeloid leukemia cells, and transcriptomics and phosphoproteomics profiling of acute degradation of CDK6 enabled dynamic mapping of its immediate role in coordinating signaling and transcription. Brand et al. describe BSJ-03-123, a degrader with proteome-wide selectivity for CDK6. Specificity emerges from differential ternary complex formation with the E3 ligase CRL4CRBN. BSJ-03-123 exploits a dependency of AML cells on CDK6, and rapid degradation allowed assaying the role of CDK6 in coordinating signaling and gene control in AML.
Discovery of a Napabucasin PROTAC as an Effective Degrader of the E3 Ligase ZFP91
Hanafi, Maha,Chen, Xinde,Neamati, Nouri
, p. 1626 - 1648 (2021)
Napabucasin, undergoing multiple clinical trials, was reported to inhibit the signal transducer and transcription factor 3 (STAT3). To better elucidate its mechanism of action, we designed a napabucasin-based proteolysis targeting chimera (PROTAC), XD2-149 that resulted in inhibition of STAT3 signaling in pancreatic cancer cell lines without inducing proteasome-dependent degradation of STAT3. Proteomics analysis of XD2-149 revealed the downregulation of the E3 ubiquitin-protein ligase ZFP91. XD2-149 degrades ZFP91 with DC50 values in the nanomolar range. The cytotoxicity of XD2-149 was significantly, but not fully, reduced with ZFP91 knockdown providing evidence for its multi-targeted mechanism of action. The NQO1 inhibitor, dicoumarol, rescued the cytotoxicity of XD2-149 but not ZFP91 degradation, suggesting that the NQO1-induced cell death is independent of ZFP91. ZFP91 plays a role in tumorigenesis and is involved in multiple oncogenic pathways including NF-κB and HIF-1α.
Targeting of the FOXM1 Oncoprotein by E3 Ligase-Assisted Degradation
Li, Guolong,Lin, Xin,Luo, Guoshun,Vega-Medina, Antonio,Wei, Hanlin,Xiang, Hua,Xiao, Maoxu,Velázquez-Martínez, Carlos A.
, p. 17098 - 17114 (2021/12/06)
The transcription factor FOXM1 that regulates multiple proliferation-related genes through selective protein-DNA and protein-protein interactions is now considered an attractive oncotarget. There are several small-molecule inhibitors that indirectly suppr
Traceless Staudinger ligation enabled parallel synthesis of proteolysis targeting chimera linker variants
Bemis, Troy A.,La Clair, James J.,Burkart, Michael D.
, p. 1026 - 1029 (2021/02/06)
A parallel, one-pot assembly approach to proteolysis targeting chimeras (PROTACs) is demonstrated utilizing activated esters generatedin situ, and traceless Staudinger ligation chemistry. The method described allows for rapid structure-activity relationship studies of PROTAC linker variants. Two previously studied systems, cereblon and BRD4 degraders, are examined as test cases for the synthetic method. The two related strategies to assemble PROTAC linker variants discussed can accommodate the chromotographic separations capabilities of labs of many sizes and incorporates commercially available degrader building blocks, thereby easing synthetic entry into PROTAC chemical space.
