5wo4 - Revision history

OCA at 14:32, 6 March 2024

2024-03-06T14:32:20Z

←Older revision		Revision as of 14:32, 6 March 2024
Line 1:		Line 1:

	==JAK1 complexed with compound 28==		==JAK1 complexed with compound 28==
-	<StructureSection load='5wo4' size='340' side='right' caption='[[5wo4]], [[Resolution\|resolution]] 1.84Å' scene=''>	+	<StructureSection load='5wo4' size='340' side='right'caption='[[5wo4]], [[Resolution\|resolution]] 1.84Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[5wo4]] 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=5WO4 OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=5WO4 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[5wo4]] 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=5WO4 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5WO4 FirstGlance]. <br>
-	</td></tr><tr id='~~ligand~~'><td class="sblockLbl"><b>[[~~Ligand~~\|~~Ligands~~:]]</b></td><td class="sblockDat">~~<scene name='pdbligand=B7V:3~~-[~~(4-chloro-3-methoxyphenyl)amino~~]-1~~-[(3R,4S)-4-cyanooxan-3-yl]-1H-pyrazole-4-carboxamide'>B7V</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]] 1.84Å</td></tr>
-	<tr id='~~NonStdRes~~'><td class="sblockLbl"><b>[[~~Non-Standard_Residue~~\|~~NonStd Res~~:]]</b></td><td class="sblockDat"><scene name='pdbligand=~~PTR~~:O-~~PHOSPHOTYROSINE'>PTR</scene></td></tr>~~	+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=B7V:3-[(4-chloro-3-methoxyphenyl)amino]-1-[(3R,4S)-4-cyanooxan-3-yl]-1H-pyrazole-4-carboxamide'>B7V</scene>, <scene name='pdbligand=PTR:O-PHOSPHOTYROSINE'>PTR</scene></td></tr>
-	~~<tr id='gene'><td class="sblockLbl"><b>~~[[~~Gene\|Gene:~~]~~]</b~~></td>~~<td class="sblockDat">JAK1~~, ~~JAK1A, JAK1B ([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=5wo4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5wo4 OCA], [https://pdbe.org/5wo4 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5wo4 RCSB], [https://www.ebi.ac.uk/pdbsum/5wo4 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5wo4 ProSAT]</span></td></tr>
-	~~<tr id~~='~~activity'><td class~~=~~"sblockLbl"><b>Activity~~:~~</b></td><td class="sblockDat"><span class='plainlinks~~'>~~[http://en.wikipedia.org/wiki/Non-specific_protein-tyrosine_kinase Non-specific protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.2 2.7.10.2]~~ </~~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=5wo4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5wo4 OCA], [~~http~~://pdbe.org/5wo4 PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=5wo4 RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/5wo4 PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=5wo4 ProSAT]</span></td></tr>	+
	</table>		</table>
	== Function ==		== Function ==
-	[~~[http~~://www.uniprot.org/uniprot/JAK1_HUMAN JAK1_HUMAN]] Tyrosine kinase of the non-receptor type, involved in the IFN-alpha/beta/gamma signal pathway. Kinase partner for the interleukin (IL)-2 receptor.	+	[https://www.uniprot.org/uniprot/JAK1_HUMAN JAK1_HUMAN] Tyrosine kinase of the non-receptor type, involved in the IFN-alpha/beta/gamma signal pathway. Kinase partner for the interleukin (IL)-2 receptor.
-	~~<div style="background-color:#fffaf0;">~~	+
-	~~== Publication Abstract from PubMed ==~~	+
-	The discovery of a potent selective low dose Janus kinase 1 (JAK1) inhibitor suitable for clinical evaluation is described. As part of an overall goal to minimize dose, we pursued a medicinal chemistry strategy focused on optimization of key parameters that influence dose size, including lowering human Clint and increasing intrinsic potency, bioavailability, and solubility. To impact these multiple parameters simultaneously, we used lipophilic ligand efficiency as a key metric to track changes in the physicochemical properties of our analogs, which led to improvements in overall compound quality. In parallel, structural information guided advancements in JAK1 selectivity by informing on new vector space, which enabled the discovery of a unique key amino acid difference between JAK1 (Glu966) and JAK2 (Asp939). This difference was exploited to consistently produce analogs with the best balance of JAK1 selectivity, efficacy, and projected human dose, ultimately culminating in the discovery of compound 28.	+

-	The Discovery of 3-((4-Chloro-3-methoxyphenyl)amino)-1-((3R,4S)-4-cyanotetrahydro-2H-pyran-3-yl)-1 H-pyrazole-4-carboxamide, a Highly Ligand Efficient and Efficacious Janus Kinase 1 Selective Inhibitor with Favorable Pharmacokinetic Properties.,Siu T, Brubaker J, Fuller P, Torres L, Zeng H, Close J, Mampreian DM, Shi F, Liu D, Fradera X, Johnson K, Bays N, Kadic E, He F, Goldenblatt P, Shaffer L, Patel SB, Lesburg CA, Alpert C, Dorosh L, Deshmukh SV, Yu H, Klappenbach J, Elwood F, Dinsmore CJ, Fernandez R, Moy L, Young JR J Med Chem. 2017 Dec 4. doi: 10.1021/acs.jmedchem.7b01135. PMID:29156136<ref>PMID:29156136</ref>	+	==See Also==
-		+	*[[Janus kinase 3D structures\|Janus kinase 3D structures]]
-	~~From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>~~	+
-	~~</div>~~	+
-	~~<div class~~=~~"pdbe-citations 5wo4" style~~=~~"background-color:#fffaf0;"></div>~~	+
-	~~== References~~ ==	+
-	~~<references/>~~	+
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Human~~]]	+	[[Category: Homo sapiens]]
-	[[Category: ~~Non-specific protein-tyrosine kinase~~]]	+	[[Category: Large Structures]]
-	[[Category: Lesburg~~, C A~~]]	+	[[Category: Lesburg CA]]
-	[[Category: Patel~~, S B]]~~	+	[[Category: Patel SB]]
-	~~[[Category: Protein tyrosine kinase]]~~	+
-	~~[[Category: Transferase~~]]	+

OCA at 07:35, 13 December 2017

2017-12-13T07:35:35Z

←Older revision		Revision as of 07:35, 13 December 2017
Line 3:		Line 3:
	<StructureSection load='5wo4' size='340' side='right' caption='[[5wo4]], [[Resolution\|resolution]] 1.84Å' scene=''>		<StructureSection load='5wo4' size='340' side='right' caption='[[5wo4]], [[Resolution\|resolution]] 1.84Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[5wo4]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5WO4 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5WO4 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[5wo4]] 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=5WO4 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5WO4 FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=B7V:3-[(4-chloro-3-methoxyphenyl)amino]-1-[(3R,4S)-4-cyanooxan-3-yl]-1H-pyrazole-4-carboxamide'>B7V</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=B7V:3-[(4-chloro-3-methoxyphenyl)amino]-1-[(3R,4S)-4-cyanooxan-3-yl]-1H-pyrazole-4-carboxamide'>B7V</scene></td></tr>
	<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue\|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=PTR:O-PHOSPHOTYROSINE'>PTR</scene></td></tr>		<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue\|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=PTR:O-PHOSPHOTYROSINE'>PTR</scene></td></tr>
		+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">JAK1, JAK1A, JAK1B ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Non-specific_protein-tyrosine_kinase Non-specific protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.2 2.7.10.2] </span></td></tr>		<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Non-specific_protein-tyrosine_kinase Non-specific protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.2 2.7.10.2] </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=5wo4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5wo4 OCA], [http://pdbe.org/5wo4 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5wo4 RCSB], [http://www.ebi.ac.uk/pdbsum/5wo4 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5wo4 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=5wo4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5wo4 OCA], [http://pdbe.org/5wo4 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5wo4 RCSB], [http://www.ebi.ac.uk/pdbsum/5wo4 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5wo4 ProSAT]</span></td></tr>
Line 24:		Line 25:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Human]]
	[[Category: Non-specific protein-tyrosine kinase]]		[[Category: Non-specific protein-tyrosine kinase]]
	[[Category: Lesburg, C A]]		[[Category: Lesburg, C A]]

OCA at 07:18, 6 December 2017

2017-12-06T07:18:11Z

←Older revision		Revision as of 07:18, 6 December 2017
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry~~ 5wo4 is ~~ON HOLD until Paper~~ Publication	+	==JAK1 complexed with compound 28==
		+	<StructureSection load='5wo4' size='340' side='right' caption='[[5wo4]], [[Resolution\|resolution]] 1.84Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[5wo4]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5WO4 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5WO4 FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=B7V:3-[(4-chloro-3-methoxyphenyl)amino]-1-[(3R,4S)-4-cyanooxan-3-yl]-1H-pyrazole-4-carboxamide'>B7V</scene></td></tr>
		+	<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue\|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=PTR:O-PHOSPHOTYROSINE'>PTR</scene></td></tr>
		+	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Non-specific_protein-tyrosine_kinase Non-specific protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.2 2.7.10.2] </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=5wo4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5wo4 OCA], [http://pdbe.org/5wo4 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5wo4 RCSB], [http://www.ebi.ac.uk/pdbsum/5wo4 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5wo4 ProSAT]</span></td></tr>
		+	</table>
		+	== Function ==
		+	[[http://www.uniprot.org/uniprot/JAK1_HUMAN JAK1_HUMAN]] Tyrosine kinase of the non-receptor type, involved in the IFN-alpha/beta/gamma signal pathway. Kinase partner for the interleukin (IL)-2 receptor.
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	The discovery of a potent selective low dose Janus kinase 1 (JAK1) inhibitor suitable for clinical evaluation is described. As part of an overall goal to minimize dose, we pursued a medicinal chemistry strategy focused on optimization of key parameters that influence dose size, including lowering human Clint and increasing intrinsic potency, bioavailability, and solubility. To impact these multiple parameters simultaneously, we used lipophilic ligand efficiency as a key metric to track changes in the physicochemical properties of our analogs, which led to improvements in overall compound quality. In parallel, structural information guided advancements in JAK1 selectivity by informing on new vector space, which enabled the discovery of a unique key amino acid difference between JAK1 (Glu966) and JAK2 (Asp939). This difference was exploited to consistently produce analogs with the best balance of JAK1 selectivity, efficacy, and projected human dose, ultimately culminating in the discovery of compound 28.

-	~~Authors~~:	+	The Discovery of 3-((4-Chloro-3-methoxyphenyl)amino)-1-((3R,4S)-4-cyanotetrahydro-2H-pyran-3-yl)-1 H-pyrazole-4-carboxamide, a Highly Ligand Efficient and Efficacious Janus Kinase 1 Selective Inhibitor with Favorable Pharmacokinetic Properties.,Siu T, Brubaker J, Fuller P, Torres L, Zeng H, Close J, Mampreian DM, Shi F, Liu D, Fradera X, Johnson K, Bays N, Kadic E, He F, Goldenblatt P, Shaffer L, Patel SB, Lesburg CA, Alpert C, Dorosh L, Deshmukh SV, Yu H, Klappenbach J, Elwood F, Dinsmore CJ, Fernandez R, Moy L, Young JR J Med Chem. 2017 Dec 4. doi: 10.1021/acs.jmedchem.7b01135. PMID:29156136<ref>PMID:29156136</ref>

-	~~Description~~:	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	[[Category: ~~Unreleased Structures~~]]	+	</div>
		+	<div class="pdbe-citations 5wo4" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Non-specific protein-tyrosine kinase]]
		+	[[Category: Lesburg, C A]]
		+	[[Category: Patel, S B]]
		+	[[Category: Protein tyrosine kinase]]
		+	[[Category: Transferase]]

OCA: Protected "5wo4" [edit=sysop:move=sysop]

2017-09-27T15:01:27Z

Protected "5wo4" [edit=sysop:move=sysop]

←Older revision

Revision as of 15:01, 27 September 2017

OCA: New page: '''Unreleased structure''' The entry 5wo4 is ON HOLD until Paper Publication Authors: Description: Category: Unreleased Structures

2017-09-27T15:01:26Z

New page: '''Unreleased structure''' The entry 5wo4 is ON HOLD until Paper Publication Authors: Description: Category: Unreleased Structures

New page

'''Unreleased structure'''

The entry 5wo4 is ON HOLD until Paper Publication

Authors:

Description:
[[Category: Unreleased Structures]]