178446-02-1Relevant articles and documents
DCAF11 Supports Targeted Protein Degradation by Electrophilic Proteolysis-Targeting Chimeras
Zhang, Xiaoyu,Luukkonen, Lena M.,Eissler, Christie L.,Crowley, Vincent M.,Yamashita, Yu,Schafroth, Michael A.,Kikuchi, Shota,Weinstein, David S.,Symons, Kent T.,Nordin, Brian E.,Rodriguez, Joe L.,Wucherpfennig, Thomas G.,Bauer, Ludwig G.,Dix, Melissa M.,Stamos, Dean,Kinsella, Todd M.,Simon, Gabriel M.,Baltgalvis, Kristen A.,Cravatt, Benjamin F.
supporting information, p. 5141 - 5149 (2021/05/04)
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.
Targeted Covalent Inhibition of Plasmodium FK506 Binding Protein 35
Atack, Thomas C.,Raymond, Donald D.,Blomquist, Christa A.,Pasaje, Charisse Flerida,McCarren, Patrick R.,Moroco, Jamie,Befekadu, Henock B.,Robinson, Foxy P.,Pal, Debjani,Esherick, Lisl Y.,Ianari, Alessandra,Niles, Jacquin C.,Sellers, William R.
, p. 2131 - 2138 (2020/12/17)
FK506-binding protein 35, FKBP35, has been implicated as an essential malarial enzyme. Rapamycin and FK506 exhibit antiplasmodium activity in cultured parasites. However, due to the highly conserved nature of the binding pockets of FKBPs and the immunosuppressive properties of these drugs, there is a need for compounds that selectively inhibit FKBP35 and lack the undesired side effects. In contrast to human FKBPs, FKBP35 contains a cysteine, C106, adjacent to the rapamycin binding pocket, providing an opportunity to develop targeted covalent inhibitors of Plasmodium FKBP35. Here, we synthesize inhibitors of FKBP35, show that they directly bind FKBP35 in a model cellular setting, selectively covalently modify C106, and exhibit antiplasmodium activity in blood-stage cultured parasites.
IMMUNOPHILIN BINDING AGENTS AND USES THEREOF
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Paragraph 1254; 1267-1268, (2020/08/22)
Described herein, inter alia, are immunophilin binding compounds and methods of treating CNS diseases, including co-administering outside the CNS of a subject an anti-CNS disease drug and a compound described herein.
Introducing aldehyde functionality to proteins using ligand-directed affinity labeling
Fung, Yi Man Eva,Huang, Yiran,Li, Xiaoyu,Peng, Jianzhao,Song, Yinan,Xiong, Feng
supporting information, p. 6134 - 6137 (2020/06/10)
Aldehyde is a versatile chemical handle for protein modification. Although many methods have been developed to label proteins with aldehyde, target-specific methods amenable to endogenous proteins are limited. Here, we report a simple affinity probe strategy to introduce aldehydes to native proteins. Notably, the probe contains a latent aldehyde functionality that is only exposed upon target binding, thereby enabling a one-pot labeling procedure.
PROTEASE INHIBITORS
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Page/Page column 106; 107, (2010/08/04)
Compounds useful as protease inhibitors are provided, as are methods of use and preparation of such compounds and compositions containing such compounds. In one embodiment, the compounds are useful for inhibiting HIV protease enzymes, and are therefore useful in slowing the proliferation of HIV.
Synthesis and activity of bivalent FKBP12 ligands for the regulated dimerization of proteins
Keenan, Terence,Yaeger, David R.,Courage, Nancy L.,Rollins, Carl T.,Pavone, Mary Ellen,Rivera, Victor M.,Yang, Wu,Guo, Tao,Amara, Jane F.,Clackson, Tim,Gilman, Michael,Holt, Dennis A.
, p. 1309 - 1335 (2007/10/03)
The total synthesis and in vitro activities of a series of chemical inducers of dimerization (CIDs) is described. The use of small-molecule CIDs to control the dimerization of engineered FKBP12-containing fusion proteins has been demonstrated to have broad utility in biological research as well as potential medical applications in gene and cell therapies. The facility and flexibility of preparation make this new class of wholly synthetic compounds exceptionally versatile tools for the study of intracellular signaling events mediated by protein-protein interactions or protein localization. While some congeners possess potency comparable to or better than the first generation natural product-derived CID, FK1012, structure-activity relationships are complex and underscore the need for application-specific compound optimizations. Copyright (C) 1998 Elsevier Science Ltd.
