6oqn - Revision history

OCA at 14:52, 13 March 2024

OCA — Wed, 13 Mar 2024 14:52:51 GMT

←Older revision		Revision as of 14:52, 13 March 2024
Line 3:		Line 3:
	<StructureSection load='6oqn' size='340' side='right'caption='[[6oqn]], [[Resolution\|resolution]] 1.70Å' scene=''>		<StructureSection load='6oqn' size='340' side='right'caption='[[6oqn]], [[Resolution\|resolution]] 1.70Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[6oqn]] is a 2 chain structure with sequence from [~~http~~://en.wikipedia.org/wiki/~~Human Human~~]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6OQN OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=6OQN FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[6oqn]] is a 2 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=6OQN OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6OQN FirstGlance]. <br>
-	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=N0P:(4S)-5-chloro-2,3,7,8,9,10,11,12-octahydro-3H,5H,14H-spiro[1,19-etheno-16lambda~6~-[1,4]oxazepino[3,4-i][1,4,5,10]oxathiadiazacyclohexadecine-4,1-indene]-16,16,18(15H,17H)-trione'>N0P</scene>~~</td></tr>~~	+	</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models\|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution\|Resolution]] 1.7Å</td></tr>
-	~~<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[6o6g\|6o6g]], [[6o6f\|6o6f]], [[6oqb\|6oqb]], [[6oqc\|6oqc]], [[6oqd\|6oqd]]</td></tr>~~	+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=N0P:(4S)-5-chloro-2,3,7,8,9,10,11,12-octahydro-3H,5H,14H-spiro[1,19-etheno-16lambda~6~-[1,4]oxazepino[3,4-i][1,4,5,10]oxathiadiazacyclohexadecine-4,1-indene]-16,16,18(15H,17H)-trione'>N0P</scene></td></tr>
-	~~<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">MCL1, BCL2L3 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])~~</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=6oqn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6oqn OCA], [https://pdbe.org/6oqn PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6oqn RCSB], [https://www.ebi.ac.uk/pdbsum/6oqn PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6oqn ProSAT]</span></td></tr>
-	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=6oqn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6oqn OCA], [~~http~~://pdbe.org/6oqn PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=6oqn RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/6oqn PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=6oqn ProSAT]</span></td></tr>	+
	</table>		</table>
	== Function ==		== Function ==
-	[~~[http~~://www.uniprot.org/uniprot/MCL1_HUMAN MCL1_HUMAN]] Involved in the regulation of apoptosis versus cell survival, and in the maintenance of viability but not of proliferation. Mediates its effects by interactions with a number of other regulators of apoptosis. Isoform 1 inhibits apoptosis. Isoform 2 promotes apoptosis.<ref>PMID:10766760</ref>	+	[https://www.uniprot.org/uniprot/MCL1_HUMAN MCL1_HUMAN] Involved in the regulation of apoptosis versus cell survival, and in the maintenance of viability but not of proliferation. Mediates its effects by interactions with a number of other regulators of apoptosis. Isoform 1 inhibits apoptosis. Isoform 2 promotes apoptosis.<ref>PMID:10766760</ref>
-	~~<div style="background-color:#fffaf0;">~~	+
-	~~== Publication Abstract from PubMed ==~~	+
-	The prosurvival BCL2 family member MCL1 is frequently dysregulated in cancer. To overcome the significant challenges associated with inhibition of MCL1 protein-protein interactions, we rigorously applied small-molecule conformational restriction, which culminated in the discovery of AMG 176, the first selective MCL1 inhibitor to be studied in humans. We demonstrate that MCL1 inhibition induces a rapid and committed step toward apoptosis in subsets of hematologic cancer cell lines, tumor xenograft models, and primary patient samples. With the use of a human MCL1 knock-in mouse, we demonstrate that MCL1 inhibition at active doses of AMG 176 is tolerated and correlates with clear pharmacodynamic effects, demonstrated by reductions in B cells, monocytes, and neutrophils. Furthermore, the combination of AMG 176 and venetoclax is synergistic in acute myeloid leukemia (AML) tumor models and in primary patient samples at tolerated doses. These results highlight the therapeutic promise of AMG 176 and the potential for combinations with other BH3 mimetics. SIGNIFICANCE: AMG 176 is a potent, selective, and orally bioavailable MCL1 inhibitor that induces a rapid commitment to apoptosis in models of hematologic malignancies. The synergistic combination of AMG 176 and venetoclax demonstrates robust activity in models of AML at tolerated doses, highlighting the promise of BH3-mimetic combinations in hematologic cancers.See related commentary by Leber et al., p. 1511.This article is highlighted in the In This Issue feature, p. 1494.	+

-	~~AMG 176, a Selective MCL1 Inhibitor, Is Effective in Hematologic Cancer Models Alone and in Combination with Established Therapies.,Caenepeel S, Brown SP, Belmontes~~ B~~, Moody G, Keegan KS, Chui D, Whittington DA, Huang X, Poppe L, Cheng AC, Cardozo M, Houze J, Li Y, Lucas~~ B, Paras NA, Wang X, Taygerly JP, Vimolratana M, Zancanella M, Zhu L, Cajulis E, Osgood T, Sun J, Damon L, Egan RK, Greninger P, McClanaghan JD, Gong J, Moujalled D, Pomilio G, Beltran P, Benes CH, Roberts AW, Huang DC, Wei A, Canon J, Coxon A, Hughes PE Cancer Discov. 2018 Dec;8(12):1582-1597. doi: 10.1158/2159-8290.CD-18-0387. Epub , 2018 Sep 25. PMID:30254093<ref>PMID:30254093</ref>	+	==See Also==
-		+	*[[B-cell lymphoma proteins 3D structures\|B-cell lymphoma proteins 3D structures]]
-	~~From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>~~	+
-	~~</div>~~	+
-	~~<div class="pdbe-citations 6oqn" style="background~~-~~color:#fffaf0;"></div>~~	+
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Human~~]]	+	[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: Huang, X]]	+	[[Category: Huang X]]
-	~~[[Category: Apoptosis]]~~	+
-	~~[[Category: Inhibitor]]~~	+
-	~~[[Category: Protein-protein interaction~~]]	+

OCA at 07:36, 21 May 2019

OCA — Tue, 21 May 2019 07:36:30 GMT

←Older revision		Revision as of 07:36, 21 May 2019
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry~~ 6oqn is ~~ON HOLD~~	+	==Crystal structure of Mcl1 with inhibitor 7==
		+	<StructureSection load='6oqn' size='340' side='right'caption='[[6oqn]], [[Resolution\|resolution]] 1.70Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[6oqn]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6OQN OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6OQN FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=N0P:(4S)-5-chloro-2,3,7,8,9,10,11,12-octahydro-3H,5H,14H-spiro[1,19-etheno-16lambda~6~-[1,4]oxazepino[3,4-i][1,4,5,10]oxathiadiazacyclohexadecine-4,1-indene]-16,16,18(15H,17H)-trione'>N0P</scene></td></tr>
		+	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[6o6g\|6o6g]], [[6o6f\|6o6f]], [[6oqb\|6oqb]], [[6oqc\|6oqc]], [[6oqd\|6oqd]]</td></tr>
		+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">MCL1, BCL2L3 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
		+	<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6oqn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6oqn OCA], [http://pdbe.org/6oqn PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6oqn RCSB], [http://www.ebi.ac.uk/pdbsum/6oqn PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6oqn ProSAT]</span></td></tr>
		+	</table>
		+	== Function ==
		+	[[http://www.uniprot.org/uniprot/MCL1_HUMAN MCL1_HUMAN]] Involved in the regulation of apoptosis versus cell survival, and in the maintenance of viability but not of proliferation. Mediates its effects by interactions with a number of other regulators of apoptosis. Isoform 1 inhibits apoptosis. Isoform 2 promotes apoptosis.<ref>PMID:10766760</ref>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	The prosurvival BCL2 family member MCL1 is frequently dysregulated in cancer. To overcome the significant challenges associated with inhibition of MCL1 protein-protein interactions, we rigorously applied small-molecule conformational restriction, which culminated in the discovery of AMG 176, the first selective MCL1 inhibitor to be studied in humans. We demonstrate that MCL1 inhibition induces a rapid and committed step toward apoptosis in subsets of hematologic cancer cell lines, tumor xenograft models, and primary patient samples. With the use of a human MCL1 knock-in mouse, we demonstrate that MCL1 inhibition at active doses of AMG 176 is tolerated and correlates with clear pharmacodynamic effects, demonstrated by reductions in B cells, monocytes, and neutrophils. Furthermore, the combination of AMG 176 and venetoclax is synergistic in acute myeloid leukemia (AML) tumor models and in primary patient samples at tolerated doses. These results highlight the therapeutic promise of AMG 176 and the potential for combinations with other BH3 mimetics. SIGNIFICANCE: AMG 176 is a potent, selective, and orally bioavailable MCL1 inhibitor that induces a rapid commitment to apoptosis in models of hematologic malignancies. The synergistic combination of AMG 176 and venetoclax demonstrates robust activity in models of AML at tolerated doses, highlighting the promise of BH3-mimetic combinations in hematologic cancers.See related commentary by Leber et al., p. 1511.This article is highlighted in the In This Issue feature, p. 1494.

-	~~Authors:~~ Huang, X.	+	AMG 176, a Selective MCL1 Inhibitor, Is Effective in Hematologic Cancer Models Alone and in Combination with Established Therapies.,Caenepeel S, Brown SP, Belmontes B, Moody G, Keegan KS, Chui D, Whittington DA, Huang X, Poppe L, Cheng AC, Cardozo M, Houze J, Li Y, Lucas B, Paras NA, Wang X, Taygerly JP, Vimolratana M, Zancanella M, Zhu L, Cajulis E, Osgood T, Sun J, Damon L, Egan RK, Greninger P, McClanaghan JD, Gong J, Moujalled D, Pomilio G, Beltran P, Benes CH, Roberts AW, Huang DC, Wei A, Canon J, Coxon A, Hughes PE Cancer Discov. 2018 Dec;8(12):1582-1597. doi: 10.1158/2159-8290.CD-18-0387. Epub , 2018 Sep 25. PMID:30254093<ref>PMID:30254093</ref>

-	~~Description: Crystal structure~~ of ~~Mcl1 with inhibitor 7~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	[[Category: ~~Unreleased~~ Structures]]	+	</div>
		+	<div class="pdbe-citations 6oqn" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Human]]
		+	[[Category: Large Structures]]
	[[Category: Huang, X]]		[[Category: Huang, X]]
		+	[[Category: Apoptosis]]
		+	[[Category: Inhibitor]]
		+	[[Category: Protein-protein interaction]]

OCA: Protected "6oqn" [edit=sysop:move=sysop]

OCA — Fri, 10 May 2019 07:58:16 GMT

Protected "6oqn" [edit=sysop:move=sysop]

←Older revision

Revision as of 07:58, 10 May 2019

OCA: New page: '''Unreleased structure''' The entry 6oqn is ON HOLD Authors: Huang, X. Description: Crystal structure of Mcl1 with inhibitor 7 Category: Unreleased Structures [[Category: Huang, X...

OCA — Fri, 10 May 2019 07:58:13 GMT

New page: '''Unreleased structure''' The entry 6oqn is ON HOLD Authors: Huang, X. Description: Crystal structure of Mcl1 with inhibitor 7 Category: Unreleased Structures [[Category: Huang, X...

New page

'''Unreleased structure'''

The entry 6oqn is ON HOLD

Authors: Huang, X.

Description: Crystal structure of Mcl1 with inhibitor 7
[[Category: Unreleased Structures]]
[[Category: Huang, X]]