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• W3119753669 abstract "Targeted protein degradation is an emerging technology for drug development. An article published in Nature reported a novel mechanism of targeted protein degradation triggered by small-molecule-induced polymerization of the oncogenic transcription factor BCL6. Targeted protein degradation is an emerging technology for drug development. An article published in Nature reported a novel mechanism of targeted protein degradation triggered by small-molecule-induced polymerization of the oncogenic transcription factor BCL6. Development of selective inhibitors against oncogenic proteins has been a gold standard for small-molecule drug development. In some cases, inhibitors with an activity to induce protein degradation are serendipitously obtained, providing a basis for a better ability to suppress target proteins in cells. For example, fulvestrant and inhibitor of apoptosis protein (IAP) antagonists degrade estrogen receptor-α (ERα) and IAPs, respectively. Introduction of a hydrophobic tag, like fulvestrant, to the protein surface can induce degradation but of limited proteins. IAP antagonists induce RING-mediated auto-ubiquitylation and proteasomal degradation of cIAP1/2. Therefore, these degradation mechanisms cannot be applied to many other proteins. The degradation of target proteins is more generally and prominently achieved by chimeric molecules such as PROTACs and SNIPERs and by E3 modulators including thalidomide, pomalidomide, and indisulam (Burslem and Crews, 2017Burslem G.M. Crews C.M. Small-Molecule Modulation of Protein Homeostasis.Chem. Rev. 2017; 117: 11269-11301Crossref PubMed Scopus (120) Google Scholar; Chamberlain and Hamann, 2019Chamberlain P.P. Hamann L.G. Development of targeted protein degradation therapeutics.Nat. Chem. Biol. 2019; 15: 937-944Crossref PubMed Scopus (106) Google Scholar; Naito et al., 2019Naito M. Ohoka N. Shibata N. SNIPERs-Hijacking IAP activity to induce protein degradation.Drug Discov. Today. Technol. 2019; 31: 35-42Crossref PubMed Scopus (45) Google Scholar). These degrader molecules directly stick a target protein on an E3 ubiquitin ligase to induce the ubiquitylation and subsequent degradation by the proteasome (Figure 1A). In addition, selective inhibitors of deubiquitylase induce degradation of target proteins that depend on the deubiquitylation for maintenance of the protein levels in cells (Shibata et al., 2020Shibata N. Ohoka N. Tsuji G. Demizu Y. Miyawaza K. Ui-Tei K. Akiyama T. Naito M. Deubiquitylase USP25 prevents degradation of BCR-ABL protein and ensures proliferation of Ph-positive leukemia cells.Oncogene. 2020; 39: 3867-3878Crossref Scopus (7) Google Scholar). Inducing targeted protein degradation by small molecules is attracting increasing attention as a novel approach for drug development (Chamberlain and Hamann, 2019Chamberlain P.P. Hamann L.G. Development of targeted protein degradation therapeutics.Nat. Chem. Biol. 2019; 15: 937-944Crossref PubMed Scopus (106) Google Scholar). B cell lymphoma 6 (BCL6) is a transcriptional repressor required for rapid proliferation and genomic recombination in normal B lymphocytes to ensure affinity maturation of antibodies in the germinal center (Hatzi and Melnick, 2014Hatzi K. Melnick A. Breaking bad in the germinal center: how deregulation of BCL6 contributes to lymphomagenesis.Trends Mol. Med. 2014; 20: 343-352Abstract Full Text Full Text PDF PubMed Scopus (104) Google Scholar). Aberrant expression of BCL6 due to translocations of heterologous promoter elements or promoter point mutations in the BCL6 locus is frequently observed in B cell malignancies including diffuse large B cell lymphoma (DLBCL), and most B cell lymphomas are dependent on BCL6, indicating that BCL6 is a promising target to treat B cell malignancies. Because the interaction of corepressors to broad complex/tramtrack/bric-a-brac (BTB) domain of BCL6 is required for the repressor function, small molecules that disrupt the interaction between the BCL6 BTB domain and corepressors have been developed, which inhibit the proliferation of DLBCL in vitro and in vivo (Cerchietti et al., 2010Cerchietti L.C. Ghetu A.F. Zhu X. Da Silva G.F. Zhong S. Matthews M. Bunting K.L. Polo J.M. Farès C. Arrowsmith C.H. et al.A small-molecule inhibitor of BCL6 kills DLBCL cells in vitro and in vivo.Cancer Cell. 2010; 17: 400-411Abstract Full Text Full Text PDF PubMed Scopus (222) Google Scholar). In an effort to develop more potent inhibitors against BCL6, a series of small molecules that interact with the BCL6 BTB domain was developed (Kerres et al., 2017Kerres N. Steurer S. Schlager S. Bader G. Berger H. Caligiuri M. Dank C. Engen J.R. Ettmayer P. Fischerauer B. et al.Chemically Induced Degradation of the Oncogenic Transcription Factor BCL6.Cell Rep. 2017; 20: 2860-2875Abstract Full Text Full Text PDF Scopus (61) Google Scholar). Intriguingly, a significant number of the inhibitors induce degradation of BCL6 in DLBCL cells, while others do not. The binding affinity to the BTB domain is not a determinant to discriminate degraders and inhibitors, and the BCL6 degradation by the representative degrader BI-3802 was not observed in cell lysates, suggesting the involvement of cellular machinery to induce BCL6 degradation. An article recently published in Nature reported a mechanism for how BI-3802 induces BCL6 degradation (Słabicki et al., 2020Słabicki M. Yoon H. Koeppel J. Nitsch L. Roy Burman S.S. Di Genua C. Donovan K.A. Sperling A.S. Hunkeler M. Tsai J.M. et al.Small-molecule-induced polymerization triggers degradation of BCL6.Nature. 2020; 588: 164-168Crossref Scopus (27) Google Scholar). The researchers developed a fluorescent reporter system to monitor BCL6 in cells and observed that BI-3802 rapidly induces BCL6 foci, followed by the disappearance of the fluorescent signal that is consistent with the degradation of BCL6 protein in cells. The BI-3802-induced foci were reversed by BI-3812, an inhibitor that cannot induce degradation and competes with BI-3802 for binding to the BTB domain. Upon BI-3802 treatment, recombinant BCL6 protein containing the BTB domain formed a filamentous structure with a sinusoidal shape in vitro. Structural analysis revealed that BI-3802 binds at a groove between BCL6 dimers and facilitates higher-order assembly through hydrophobic interactions of this compound with an adjacent BCL6 dimer. Thus, BI-3802 functions as a molecular glue to polymerize the BCL6 proteins (Figure 1B). In this model, BI-3812 with extended carboxamide group shows a steric clash to the adjacent BCL6 dimer, which could explain the inability of this compound to induce BCL6 polymerization. With the fluorescent reporter of BCL6 degradation, they also identified a VxP motif recognized by SIAH1 E3 ubiquitin ligase as an essential element for BI-3802-induced degradation (Słabicki et al., 2020Słabicki M. Yoon H. Koeppel J. Nitsch L. Roy Burman S.S. Di Genua C. Donovan K.A. Sperling A.S. Hunkeler M. Tsai J.M. et al.Small-molecule-induced polymerization triggers degradation of BCL6.Nature. 2020; 588: 164-168Crossref Scopus (27) Google Scholar). Consistently, disruption of SIAH1 renders cells resistant to growth suppression and BCL6 degradation induced by BI-3802. The association of SIAH1 with BCL6 is enhanced by BI-3802-induced polymerization. Collectively, they concluded that BI-3802 induces polymerization of BCL6 followed by sequestration into cellular foci, which facilitates ubiquitylation by SIAH1 and subsequent degradation by the proteasome (Figure 1B). In the polymerized BCL6, the VxP motif might be more accessible to SIAH1, resulting in the enhancement of SIAH1 association. Alternatively, multivalent interaction between polymerized BCL6 and SIAH1 could enhance the association, because homo-dimeric interaction of SIAH1 was observed in various experimental systems. In any case, polymerization of BCL6 triggers degradation in a highly specific manner. However, the BCL6 domains required for the degradation are not consistent between the two articles reporting the BI-3802-induced BCL6 degradation. In the first paper, deletion or mutation of carboxy-terminal zinc finger domain resulted in the complete loss of the degradation, whereas deleting the middle region containing VxP motif did not seriously affect the degradation (Kerres et al., 2017Kerres N. Steurer S. Schlager S. Bader G. Berger H. Caligiuri M. Dank C. Engen J.R. Ettmayer P. Fischerauer B. et al.Chemically Induced Degradation of the Oncogenic Transcription Factor BCL6.Cell Rep. 2017; 20: 2860-2875Abstract Full Text Full Text PDF Scopus (61) Google Scholar). Furthermore, replacing the zinc finger domain of BCL6 with basic helix-loop-helix domain from TCF4 maintained the degradation, suggesting the involvement of DNA binding in BI-3802-induced BCL6 degradation. In the second paper on the other hands, VxP motif is required for the degradation as described above, and the deletion of carboxy-terminal zinc finger did not affect the degradation in their fluorescence reporter system (Słabicki et al., 2020Słabicki M. Yoon H. Koeppel J. Nitsch L. Roy Burman S.S. Di Genua C. Donovan K.A. Sperling A.S. Hunkeler M. Tsai J.M. et al.Small-molecule-induced polymerization triggers degradation of BCL6.Nature. 2020; 588: 164-168Crossref Scopus (27) Google Scholar). These apparent discrepancies could be due to the difference in the experimental system, because GFP fusion proteins tend to localize to the cytosol which could weaken the nuclear translocation of BCL6, thereby abrogating BCL6 degradation that could take place in nuclei. Thus, although it is evident that BI-3802 induces BCL6 degradation by triggering polymerization and subsequent ubiquitylation by SIAH1 in the cytosol, it does not rule out the possibility that an additional nuclear degradation mechanism is also involved. Given the novel degradation mechanism triggered by the polymerization of BCL6, one could ask whether it can be applied more broadly to induce degradation of other proteins. Growing evidence indicates that small molecules can induce hetero-dimerization, homo-dimerization, and further polymerization of proteins (Stanton et al., 2018Stanton B.Z. Chory E.J. Crabtree G.R. Chemically induced proximity in biology and medicine.Science. 2018; 359: eaao5902Crossref PubMed Scopus (108) Google Scholar). The dimerized and polymerized proteins could provoke ubiquitylation by particular E3 ubiquitin ligases, leading to degradation (Mena et al., 2018Mena E.L. Kjolby R.A.S. Saxton R.A. Werner A. Lew B.G. Boyle J.M. Harland R. Rape M. Dimerization quality control ensures neuronal development and survival.Science. 2018; 362: eaap8236Crossref PubMed Scopus (32) Google Scholar). Of course, cellular responses other than ubiquitylation could also be invoked by the dimerized and polymerized proteins. Small molecules that glue proteins together will offer a novel playground in biology and drug development. M.N. was supported by JSPS KAKENHI grant number JP18H05502 and AMED grant number 20ak0101073h1604 . S.M. was supported by JSPS KAKENHI grant numbers JP18H05500 and JP18H04022 and AMED grant number JP20 gm1110003h0004 AMED-CREST . M.N. is a project professor supported by Eisai and a scientific advisor of Ubience. S.M. declares no competing interests." @default.
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• W3119753669 title "Gluing Proteins for Targeted Degradation" @default.
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