8qjs: Difference between revisions

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== Function ==

[https://www.uniprot.org/uniprot/ELOB_HUMAN ELOB_HUMAN] SIII, also known as elongin, is a general transcription elongation factor that increases the RNA polymerase II transcription elongation past template-encoded arresting sites. Subunit A is transcriptionally active and its transcription activity is strongly enhanced by binding to the dimeric complex of the SIII regulatory subunits B and C (elongin BC complex).<ref>PMID:7638163</ref> <ref>PMID:15590694</ref> The elongin BC complex seems to be involved as an adapter protein in the proteasomal degradation of target proteins via different E3 ubiquitin ligase complexes, including the von Hippel-Lindau ubiquitination complex CBC(VHL). By binding to BC-box motifs it seems to link target recruitment subunits, like VHL and members of the SOCS box family, to Cullin/RBX1 modules that activate E2 ubiquitination enzymes.<ref>PMID:7638163</ref> <ref>PMID:15590694</ref>

~~<div style="background-color:#fffaf0;">~~

~~== Publication Abstract from PubMed ==~~

The identification of VHL-binding proteolysis targeting chimeras (PROTACs) that potently degrade the BRM protein (also known as SMARCA2) in SW1573 cell-based experiments is described. These molecules exhibit between 10- and 100-fold degradation selectivity for BRM over the closely related paralog protein BRG1 (SMARCA4). They also selectively impair the proliferation of the H1944 "BRG1-mutant" NSCLC cell line, which lacks functional BRG1 protein and is thus highly dependent on BRM for growth, relative to the wild-type Calu6 line. In vivo experiments performed with a subset of compounds identified PROTACs that potently and selectively degraded BRM in the Calu6 and/or the HCC2302 BRG1 mutant NSCLC xenograft models and also afforded antitumor efficacy in the latter system. Subsequent PK/PD analysis established a need to achieve strong BRM degradation (>95%) in order to trigger meaningful antitumor activity in vivo. Intratumor quantitation of mRNA associated with two genes whose transcription was controlled by BRM (PLAU and KRT80) also supported this conclusion.

PROTACs Targeting BRM (SMARCA2) Afford Selective In Vivo Degradation over BRG1 (SMARCA4) and Are Active in BRG1 Mutant Xenograft Tumor Models.,Berlin M, Cantley J, Bookbinder M, Bortolon E, Broccatelli F, Cadelina G, Chan EW, Chen H, Chen X, Cheng Y, Cheung TK, Davenport K, DiNicola D, Gordon D, Hamman BD, Harbin A, Haskell R, He M, Hole AJ, Januario T, Kerry PS, Koenig SG, Li L, Merchant M, Perez-Dorado I, Pizzano J, Quinn C, Rose CM, Rousseau E, Soto L, Staben LR, Sun H, Tian Q, Wang J, Wang W, Ye CS, Ye X, Zhang P, Zhou Y, Yauch R, Dragovich PS J Med Chem. 2024 Jan 5. doi: 10.1021/acs.jmedchem.3c01781. PMID:38180485<ref>PMID:38180485</ref>

~~From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>~~

~~</div>~~

~~<div class="pdbe-citations 8qjs" style="background-color:#fffaf0;"></div>~~

== References ==

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 == Function ==
 [https://www.uniprot.org/uniprot/ELOB_HUMAN ELOB_HUMAN] SIII, also known as elongin, is a general transcription elongation factor that increases the RNA polymerase II transcription elongation past template-encoded arresting sites. Subunit A is transcriptionally active and its transcription activity is strongly enhanced by binding to the dimeric complex of the SIII regulatory subunits B and C (elongin BC complex).<ref>PMID:7638163</ref> <ref>PMID:15590694</ref>   The elongin BC complex seems to be involved as an adapter protein in the proteasomal degradation of target proteins via different E3 ubiquitin ligase complexes, including the von Hippel-Lindau ubiquitination complex CBC(VHL). By binding to BC-box motifs it seems to link target recruitment subunits, like VHL and members of the SOCS box family, to Cullin/RBX1 modules that activate E2 ubiquitination enzymes.<ref>PMID:7638163</ref> <ref>PMID:15590694</ref>
-<div style="background-color:#fffaf0;">
-== Publication Abstract from PubMed ==
-The identification of VHL-binding proteolysis targeting chimeras (PROTACs) that potently degrade the BRM protein (also known as SMARCA2) in SW1573 cell-based experiments is described. These molecules exhibit between 10- and 100-fold degradation selectivity for BRM over the closely related paralog protein BRG1 (SMARCA4). They also selectively impair the proliferation of the H1944 "BRG1-mutant" NSCLC cell line, which lacks functional BRG1 protein and is thus highly dependent on BRM for growth, relative to the wild-type Calu6 line. In vivo experiments performed with a subset of compounds identified PROTACs that potently and selectively degraded BRM in the Calu6 and/or the HCC2302 BRG1 mutant NSCLC xenograft models and also afforded antitumor efficacy in the latter system. Subsequent PK/PD analysis established a need to achieve strong BRM degradation (&gt;95%) in order to trigger meaningful antitumor activity in vivo. Intratumor quantitation of mRNA associated with two genes whose transcription was controlled by BRM (PLAU and KRT80) also supported this conclusion.
-PROTACs Targeting BRM (SMARCA2) Afford Selective In Vivo Degradation over BRG1 (SMARCA4) and Are Active in BRG1 Mutant Xenograft Tumor Models.,Berlin M, Cantley J, Bookbinder M, Bortolon E, Broccatelli F, Cadelina G, Chan EW, Chen H, Chen X, Cheng Y, Cheung TK, Davenport K, DiNicola D, Gordon D, Hamman BD, Harbin A, Haskell R, He M, Hole AJ, Januario T, Kerry PS, Koenig SG, Li L, Merchant M, Perez-Dorado I, Pizzano J, Quinn C, Rose CM, Rousseau E, Soto L, Staben LR, Sun H, Tian Q, Wang J, Wang W, Ye CS, Ye X, Zhang P, Zhou Y, Yauch R, Dragovich PS J Med Chem. 2024 Jan 5. doi: 10.1021/acs.jmedchem.3c01781. PMID:38180485<ref>PMID:38180485</ref>
-From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-</div>
-<div class="pdbe-citations 8qjs" style="background-color:#fffaf0;"></div>
 == References ==
 <references/>