8pqn - Revision history

OCA at 09:33, 20 March 2024

OCA — Wed, 20 Mar 2024 09:33:39 GMT

←Older revision		Revision as of 09:33, 20 March 2024
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	== Function ==		== Function ==
	[https://www.uniprot.org/uniprot/NQO1_HUMAN NQO1_HUMAN] The enzyme apparently serves as a quinone reductase in connection with conjugation reactions of hydroquinons involved in detoxification pathways as well as in biosynthetic processes such as the vitamin K-dependent gamma-carboxylation of glutamate residues in prothrombin synthesis.		[https://www.uniprot.org/uniprot/NQO1_HUMAN NQO1_HUMAN] The enzyme apparently serves as a quinone reductase in connection with conjugation reactions of hydroquinons involved in detoxification pathways as well as in biosynthetic processes such as the vitamin K-dependent gamma-carboxylation of glutamate residues in prothrombin synthesis.
-	<div style="background-color:#fffaf0;">
-	== Publication Abstract from PubMed ==
-	Degraders hold the promise to efficiently inactivate previously intractable disease-relevant targets. Unlike traditional inhibitors, degraders act substoichiometrically and rely on the hijacked proteolysis machinery, which can also act as an entry point for resistance. To fully harness the potential of targeted protein degradation, it is crucial to comprehend resistance mechanisms and formulate effective strategies to overcome them. We conducted a chemical screening to identify synthetic lethal vulnerabilities of cancer cells that exhibit widespread resistance to degraders. Comparative profiling followed by tailored optimization delivered the small molecule RBS-10, which shows preferential cytotoxicity against cells pan-resistant to degraders. Multiomics deconvolution of the mechanism of action revealed that RBS-10 acts as a prodrug bioactivated by the oxidoreductase enzyme NQO1, which is highly overexpressed in our resistance models. Collectively, our work informs on NQO1 as an actionable vulnerability to overcome resistance to degraders and as a biomarker to selectively exploit bioactivatable prodrugs in cancer.
-
-	Discovery and Mechanistic Elucidation of NQO1-Bioactivatable Small Molecules That Overcome Resistance to Degraders.,Barbosa BM, Sfyaki A, Rafael S, Jose-Duran F, Pous J, Sanchez-Zarzalejo C, Perez-Lopez C, Vilanova M, Cigler M, Gay M, Vilaseca M, Winter GE, Riera A, Mayor-Ruiz C Angew Chem Int Ed Engl. 2023 Dec 28:e202316730. doi: 10.1002/anie.202316730. PMID:38153885<ref>PMID:38153885</ref>
-
-	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	</div>
-	<div class="pdbe-citations 8pqn" style="background-color:#fffaf0;"></div>
-	== References ==
-	<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>

OCA at 10:26, 10 January 2024

OCA — Wed, 10 Jan 2024 10:26:15 GMT

←Older revision		Revision as of 10:26, 10 January 2024
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry~~ 8pqn is ~~ON HOLD until Paper~~ Publication	+	==NQO1 bound to RBS-10==
		+	<StructureSection load='8pqn' size='340' side='right'caption='[[8pqn]], [[Resolution\|resolution]] 3.80Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[8pqn]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8PQN OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8PQN FirstGlance]. <br>
		+	</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models\|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution\|Resolution]] 3.8Å</td></tr>
		+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=978:~{N}-[4-[(3-methylphenyl)carbonylamino]phenyl]-5-nitro-furan-2-carboxamide'>978</scene>, <scene name='pdbligand=FAD:FLAVIN-ADENINE+DINUCLEOTIDE'>FAD</scene></td></tr>
		+	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=8pqn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8pqn OCA], [https://pdbe.org/8pqn PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8pqn RCSB], [https://www.ebi.ac.uk/pdbsum/8pqn PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8pqn ProSAT]</span></td></tr>
		+	</table>
		+	== Function ==
		+	[https://www.uniprot.org/uniprot/NQO1_HUMAN NQO1_HUMAN] The enzyme apparently serves as a quinone reductase in connection with conjugation reactions of hydroquinons involved in detoxification pathways as well as in biosynthetic processes such as the vitamin K-dependent gamma-carboxylation of glutamate residues in prothrombin synthesis.
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	Degraders hold the promise to efficiently inactivate previously intractable disease-relevant targets. Unlike traditional inhibitors, degraders act substoichiometrically and rely on the hijacked proteolysis machinery, which can also act as an entry point for resistance. To fully harness the potential of targeted protein degradation, it is crucial to comprehend resistance mechanisms and formulate effective strategies to overcome them. We conducted a chemical screening to identify synthetic lethal vulnerabilities of cancer cells that exhibit widespread resistance to degraders. Comparative profiling followed by tailored optimization delivered the small molecule RBS-10, which shows preferential cytotoxicity against cells pan-resistant to degraders. Multiomics deconvolution of the mechanism of action revealed that RBS-10 acts as a prodrug bioactivated by the oxidoreductase enzyme NQO1, which is highly overexpressed in our resistance models. Collectively, our work informs on NQO1 as an actionable vulnerability to overcome resistance to degraders and as a biomarker to selectively exploit bioactivatable prodrugs in cancer.

-	~~Authors: Pous, J~~., Jose-Duran, F., ~~Mayor~~-~~Ruiz~~, C., ~~Riera~~, A.	+	Discovery and Mechanistic Elucidation of NQO1-Bioactivatable Small Molecules That Overcome Resistance to Degraders.,Barbosa BM, Sfyaki A, Rafael S, Jose-Duran F, Pous J, Sanchez-Zarzalejo C, Perez-Lopez C, Vilanova M, Cigler M, Gay M, Vilaseca M, Winter GE, Riera A, Mayor-Ruiz C Angew Chem Int Ed Engl. 2023 Dec 28:e202316730. doi: 10.1002/anie.202316730. PMID:38153885<ref>PMID:38153885</ref>

-	~~Description: NQO1 bound to RBS~~-10	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	~~[[Category~~: ~~Unreleased Structures]]~~	+	</div>
-	[[Category: ~~Riera, A~~]]	+	<div class="pdbe-citations 8pqn" style="background-color:#fffaf0;"></div>
-	[[Category: ~~Pous, J~~]]	+	== References ==
-	[[Category: Jose-Duran, F]]	+	<references/>
-	[[Category: Mayor-Ruiz, C]]	+	__TOC__
		+	</StructureSection>
		+	[[Category: Homo sapiens]]
		+	[[Category: Large Structures]]
		+	[[Category: Jose-Duran F]]
		+	[[Category: Mayor-Ruiz C]]
		+	[[Category: Pous J]]
		+	[[Category: Riera A]]

OCA at 07:20, 30 August 2023

OCA — Wed, 30 Aug 2023 07:20:09 GMT

←Older revision		Revision as of 07:20, 30 August 2023
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 8pqn is ON HOLD	+	The entry 8pqn is ON HOLD until Paper Publication

	Authors: Pous, J., Jose-Duran, F., Mayor-Ruiz, C., Riera, A.		Authors: Pous, J., Jose-Duran, F., Mayor-Ruiz, C., Riera, A.

OCA at 09:07, 2 August 2023

OCA — Wed, 02 Aug 2023 09:07:20 GMT

←Older revision		Revision as of 09:07, 2 August 2023
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 8pqn is ON HOLD ~~until sometime in the future~~	+	The entry 8pqn is ON HOLD

	Authors: Pous, J., Jose-Duran, F., Mayor-Ruiz, C., Riera, A.		Authors: Pous, J., Jose-Duran, F., Mayor-Ruiz, C., Riera, A.

OCA at 10:55, 26 July 2023

OCA — Wed, 26 Jul 2023 10:55:55 GMT

←Older revision		Revision as of 10:55, 26 July 2023
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 8pqn is ON HOLD	+	The entry 8pqn is ON HOLD until sometime in the future

	Authors: Pous, J., Jose-Duran, F., Mayor-Ruiz, C., Riera, A.		Authors: Pous, J., Jose-Duran, F., Mayor-Ruiz, C., Riera, A.

OCA: Protected "8pqn" [edit=sysop:move=sysop]

OCA — Wed, 19 Jul 2023 04:54:27 GMT

Protected "8pqn" [edit=sysop:move=sysop]

←Older revision

Revision as of 04:54, 19 July 2023

OCA: New page: '''Unreleased structure''' The entry 8pqn is ON HOLD Authors: Pous, J., Jose-Duran, F., Mayor-Ruiz, C., Riera, A. Description: NQO1 bound to RBS-10 Category: Unreleased Structures ...

OCA — Wed, 19 Jul 2023 04:54:26 GMT

New page: '''Unreleased structure''' The entry 8pqn is ON HOLD Authors: Pous, J., Jose-Duran, F., Mayor-Ruiz, C., Riera, A. Description: NQO1 bound to RBS-10 Category: Unreleased Structures ...

New page

'''Unreleased structure'''

The entry 8pqn is ON HOLD

Authors: Pous, J., Jose-Duran, F., Mayor-Ruiz, C., Riera, A.

Description: NQO1 bound to RBS-10
[[Category: Unreleased Structures]]
[[Category: Riera, A]]
[[Category: Pous, J]]
[[Category: Jose-Duran, F]]
[[Category: Mayor-Ruiz, C]]