المؤلفون: Yujun Zhao¹, Liu Liu¹, Wei Sun¹, Jianfeng Lu¹, Donna McEachern¹, Xiaoqin, Li², Shanghai Yu¹, Bernard, Denzil¹, Ochsenbein, Philippe³, Ferey, Vincent³, Carry, Jean-Christophe⁴, Deschamps, Jeffrey R.⁵, Sun, Duxin², Shaomeng Wang¹ shaomeng@umich.edu

المصدر: Journal of the American Chemical Society. 5/15/2013, Vol. 135 Issue 19, p7223-7234. 12p.

مصطلحات موضوعية: *OXINDOLES, *UBIQUITIN-protein ligase regulation, *P53 protein, *PROTEIN-protein interactions, *PROTEIN metabolism inhibitors, *DIASTEREOISOMERS, *ANTINEOPLASTIC agents

مستخلص: Small-molecule inhibitors that block the MDM2-p53 protein-protein interaction (MDM2 inhibitors) are being intensely pursued as a new therapeutic strategy for cancer treatment. We previously published a series of spirooxindole-containing compounds as a new class of MDM2 small-molecule inhibitors. We report herein a reversible ring-opening-cyclization reaction for some of these spirooxindoles, which affords four diastereomers from a single compound. Our biochemical binding data showed that the stereochemistry in this class of compounds has a major effect on their binding affinities to MDM2, with >100-fold difference between the most potent and the least potent stereoisomers. Our study has led to the identification of a set of highly potent MDM2 inhibitors with a stereochemistry that is different from that of our previously reported compounds. The most potent compound (MI-888) binds to MDM2 with a Ki value of 0.44 nM and achieves complete and long-lasting tumor regression in an animal model of human cancer. [ABSTRACT FROM AUTHOR]

المؤلفون: Kristen A. Baltgalvis, Vincent M. Crowley, Michael A. Schafroth, Brian E. Nordin, Benjamin F. Cravatt, Christie L Eissler, Joe L Rodriguez, Shota Kikuchi, Xiaoyu Zhang, Thomas G Wucherpfennig, Todd Kinsella, Kent T Symons, Melissa M. Dix, David S. Weinstein, Dean Stamos, Gabriel M. Simon, Yu Yamashita, Ludwig Bauer, Lena M Luukkonen

المصدر: J Am Chem Soc

مصطلحات موضوعية: Male, Proteasome Endopeptidase Complex, Proteolysis, Protein degradation, 010402 general chemistry, 01 natural sciences, Biochemistry, Article, Catalysis, Chimera (genetics), Colloid and Surface Chemistry, Cell Line, Tumor, medicine, Humans, Receptor, medicine.diagnostic_test, biology, Ubiquitin, Chemistry, Prostatic Neoplasms, Ubiquitin-Protein Ligase Complexes, General Chemistry, 0104 chemical sciences, Ubiquitin ligase, Cell biology, Androgen receptor, Receptors, Androgen, Cell culture, Cancer cell, biology.protein

الوصف: Ligand-induced protein degradation has emerged as a compelling approach to promote the targeted elimination of proteins from cells by directing these proteins to the ubiquitin-proteasome machinery. So far, only a limited number of E3 ligases have been found to support ligand-induced protein degradation, reflecting a dearth of E3-binding compounds for proteolysis-targeting chimera (PROTAC) design. Here, we describe a functional screening strategy performed with a focused library of candidate electrophilic PROTACs to discover bifunctional compounds that degrade proteins in human cells by covalently engaging E3 ligases. Mechanistic studies revealed that the electrophilic PROTACs act through modifying specific cysteines in DCAF11, a poorly characterized E3 ligase substrate adaptor. We further show that DCAF11-directed electrophilic PROTACs can degrade multiple endogenous proteins, including FBKP12 and the androgen receptor, in human prostate cancer cells. Our findings designate DCAF11 as an E3 ligase capable of supporting ligand-induced protein degradation via electrophilic PROTACs.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::a9801b3a3bafd3e374259ca9ad1a1524Test
https://doi.org/10.1021/jacs.1c00990Test

المؤلفون: Nathaniel J. Henning, Andrew G. Manford, Jessica N. Spradlin, Scott M. Brittain, Erika Zhang, Jeffrey M. McKenna, John A. Tallarico, Markus Schirle, Michael Rape, Daniel K. Nomura

المصدر: J Am Chem Soc

مصطلحات موضوعية: Proteasome Endopeptidase Complex, Binding Sites, Dasatinib, Fusion Proteins, bcr-abl, Ubiquitin-Protein Ligase Complexes, Cell Cycle Proteins, General Chemistry, Azepines, Triazoles, Biochemistry, Catalysis, Recombinant Proteins, Article, Cell Line, Mice, Colloid and Surface Chemistry, Acetamides, Proteolysis, Animals, Humans, Cysteine, Carrier Proteins, Protein Kinase Inhibitors, Protein Binding, Transcription Factors

الوصف: Proteolysis Targeting Chimeras (PROTACs), heterobifunctional compounds that consist of protein-targeting ligands linked to an E3 ligase recruiter, have arisen as a powerful therapeutic modality for targeted protein degradation (TPD). Despite the popularity of TPD approaches in drug discovery, only a small number of E3 ligase recruiters are available for the >600 E3 ligases that exist in human cells. Here, we have discovered a cysteine-reactive covalent ligand, EN106, that targets FEM1B, an E3 ligase recently discovered as the critical component of the cellular response to reductive stress. By targeting C186 in FEM1B, EN106 disrupts recognition of the key reductive stress substrate of FEM1B, FNIP1. We further establish that EN106 can be used as a covalent recruiter for FEM1B in TPD applications by demonstrating that a PROTAC linking EN106 to the BET Bromodomain inhibitor JQ1 or the kinase inhibitor dasatinib leads to the degradation of BRD4 and BCR-ABL, respectively. Our study showcases a covalent ligand that targets a natural E3 ligase-substrate binding site and highlights the utility of covalent ligand screening in expanding the arsenal of E3 ligase recruiters suitable for TPD applications.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::883c232f223b56eeda2a0e64db5426bfTest
https://pubmed.ncbi.nlm.nih.gov/34994556Test