7jy4 - Revision history

OCA at 15:14, 18 October 2023

OCA — Wed, 18 Oct 2023 15:14:33 GMT

←Older revision		Revision as of 15:14, 18 October 2023
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	==hALK in complex with ((1S,2S)-1-(2,4-difluorophenyl)-2-(2-(3-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenoxy)cyclopropyl)methanamine==		==hALK in complex with ((1S,2S)-1-(2,4-difluorophenyl)-2-(2-(3-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenoxy)cyclopropyl)methanamine==
-	<StructureSection load='7jy4' size='340' side='right'caption='[[7jy4]]' scene=''>	+	<StructureSection load='7jy4' size='340' side='right'caption='[[7jy4]], [[Resolution\|resolution]] 2.42Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7JY4 OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://proteopedia.org/fgij/fg.htm?mol=7JY4 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[7jy4]] is a 1 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=7JY4 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7JY4 FirstGlance]. <br>
-	</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[~~http~~://proteopedia.org/fgij/fg.htm?mol=7jy4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7jy4 OCA], [~~http~~://pdbe.org/7jy4 PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=7jy4 RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/7jy4 PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=7jy4 ProSAT]</span></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]] 2.42Å</td></tr>
		+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=W47:1-{(1S,2S)-1-(2,4-difluorophenyl)-2-[2-(3-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenoxy]cyclopropyl}methanamine'>W47</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=7jy4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7jy4 OCA], [https://pdbe.org/7jy4 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7jy4 RCSB], [https://www.ebi.ac.uk/pdbsum/7jy4 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7jy4 ProSAT]</span></td></tr>
	</table>		</table>
		+	== Disease ==
		+	[https://www.uniprot.org/uniprot/ALK_HUMAN ALK_HUMAN] Note=A chromosomal aberration involving ALK is found in a form of non-Hodgkin lymphoma. Translocation t(2;5)(p23;q35) with NPM1. The resulting chimeric NPM1-ALK protein homodimerize and the kinase becomes constitutively activated. The constitutively active fusion proteins are responsible for 5-10% of non-Hodgkin lymphomas. Note=A chromosomal aberration involving ALK is associated with inflammatory myofibroblastic tumors (IMTs). Translocation t(2;11)(p23;p15) with CARS; translocation t(2;4)(p23;q21) with SEC31A. Note=A chromosomal aberration involving ALK is associated with anaplastic large-cell lymphoma (ALCL). Translocation t(2;17)(p23;q25) with ALO17. Defects in ALK are the cause of susceptibility to neuroblastoma type 3 (NBLST3) [MIM:[https://omim.org/entry/613014 613014]. Neuroblastoma is a common neoplasm of early childhood arising from embryonic cells that form the primitive neural crest and give rise to the adrenal medulla and the sympathetic nervous system.<ref>PMID:18724359</ref> <ref>PMID:18923523</ref> <ref>PMID:18923525</ref> Note=The ALK signaling pathway plays an important role in glioblastoma, the most common malignant brain tumor of adults and one of the most lethal cancers. It regulates both glioblastoma migration and growth.
		+	== Function ==
		+	[https://www.uniprot.org/uniprot/ALK_HUMAN ALK_HUMAN] Neuronal orphan receptor tyrosine kinase that is essentially and transiently expressed in specific regions of the central and peripheral nervous systems and plays an important role in the genesis and differentiation of the nervous system. Transduces signals from ligands at the cell surface, through specific activation of the mitogen-activated protein kinase (MAPK) pathway. Phosphorylates almost exclusively at the first tyrosine of the Y-x-x-x-Y-Y motif. Following activation by ligand, ALK induces tyrosine phosphorylation of CBL, FRS2, IRS1 and SHC1, as well as of the MAP kinases MAPK1/ERK2 and MAPK3/ERK1. Acts as a receptor for ligands pleiotrophin (PTN), a secreted growth factor, and midkine (MDK), a PTN-related factor, thus participating in PTN and MDK signal transduction. PTN-binding induces MAPK pathway activation, which is important for the anti-apoptotic signaling of PTN and regulation of cell proliferation. MDK-binding induces phosphorylation of the ALK target insulin receptor substrate (IRS1), activates mitogen-activated protein kinases (MAPKs) and PI3-kinase, resulting also in cell proliferation induction. Drives NF-kappa-B activation, probably through IRS1 and the activation of the AKT serine/threonine kinase. Recruitment of IRS1 to activated ALK and the activation of NF-kappa-B are essential for the autocrine growth and survival signaling of MDK.<ref>PMID:11387242</ref> <ref>PMID:11121404</ref> <ref>PMID:11278720</ref> <ref>PMID:11809760</ref> <ref>PMID:12107166</ref> <ref>PMID:12122009</ref> <ref>PMID:15226403</ref> <ref>PMID:15908427</ref> <ref>PMID:16317043</ref> <ref>PMID:17274988</ref> <ref>PMID:16878150</ref>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	Fragment screening is frequently used for hit identification. However, there was no report starting from a small fragment for the development of an anaplastic lymphoma kinase (ALK) inhibitor, despite the number of ALK inhibitors reported. We began our research with the fragment hit F-1 and our subsequent linker design, and its docking analysis yielded novel cis-1,2,2-trisubstituted cyclopropane 1. The fragment information was integrated with a structure-based approach to improve upon the selectivity over tropomyosin receptor kinase A, leading to the potent and highly selective ALK inhibitor, 4-trifluoromethylphenoxy-cis-1,2,2-trisubstituted cyclopropane 12. This work shows that fragments become a powerful tool for both lead generation and optimization, such as the improvement of selectivity, by combining them with a structure-based drug design approach, resulting in the fast and efficient development of a novel, potent, and highly selective compound.
		+
		+	Discovery of Novel and Highly Selective Cyclopropane ALK Inhibitors through a Fragment-Assisted, Structure-Based Drug Design.,Fujimori I, Wakabayashi T, Murakami M, Okabe A, Ishii T, McGrath A, Zou H, Saikatendu KS, Imoto H ACS Omega. 2020 Nov 30;5(49):31984-32001. doi: 10.1021/acsomega.0c04900., eCollection 2020 Dec 15. PMID:33344853<ref>PMID:33344853</ref>
		+
		+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
		+	</div>
		+	<div class="pdbe-citations 7jy4" style="background-color:#fffaf0;"></div>
		+
		+	==See Also==
		+	*[[Tyrosine kinase 3D structures\|Tyrosine kinase 3D structures]]
		+	== References ==
		+	<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
	[[Category: Lane W]]		[[Category: Lane W]]

OCA at 08:14, 20 January 2021

OCA — Wed, 20 Jan 2021 08:14:24 GMT

←Older revision		Revision as of 08:14, 20 January 2021
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-	'''Unreleased structure'''

-	~~The entry 7jy4 is ON HOLD until Paper Publication~~	+	==hALK in complex with ((1S,2S)-1-(2,4-difluorophenyl)-2-(2-(3-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenoxy)cyclopropyl)methanamine==
-		+	<StructureSection load='7jy4' size='340' side='right'caption='[[7jy4]]' scene=''>
-	~~Authors: McGrath, A.P., Zou, H., Lane, W., Saikatendu, K.~~	+	== Structural highlights ==
-		+	<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7JY4 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=7JY4 FirstGlance]. <br>
-	~~Description:~~ hALK in complex with ((1S,2S)-1-(2,4-difluorophenyl)-2-(2-(3-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenoxy)cyclopropyl)methanamine	+	</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=7jy4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7jy4 OCA], [http://pdbe.org/7jy4 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=7jy4 RCSB], [http://www.ebi.ac.uk/pdbsum/7jy4 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=7jy4 ProSAT]</span></td></tr>
-	[[Category: ~~Unreleased~~ Structures]]	+	</table>
-	[[Category: ~~Zou, H~~]]	+	__TOC__
-	[[Category: ~~Saikatendu, K~~]]	+	</StructureSection>
-	[[Category: ~~Mcgrath, A.P~~]]	+	[[Category: Large Structures]]
-	[[Category: ~~Lane, W~~]]	+	[[Category: Lane W]]
		+	[[Category: McGrath AP]]
		+	[[Category: Saikatendu K]]
		+	[[Category: Zou H]]

OCA at 19:06, 28 October 2020

OCA — Wed, 28 Oct 2020 19:06:07 GMT

←Older revision		Revision as of 19:06, 28 October 2020
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	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 7jy4 is ON HOLD	+	The entry 7jy4 is ON HOLD until Paper Publication

	Authors: McGrath, A.P., Zou, H., Lane, W., Saikatendu, K.		Authors: McGrath, A.P., Zou, H., Lane, W., Saikatendu, K.

OCA at 09:08, 23 September 2020

OCA — Wed, 23 Sep 2020 09:08:45 GMT

←Older revision		Revision as of 09:08, 23 September 2020
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	Authors: McGrath, A.P., Zou, H., Lane, W., Saikatendu, K.		Authors: McGrath, A.P., Zou, H., Lane, W., Saikatendu, K.

-	Description: hALK in complex with ~~1-[~~(1R,2R)-1-(2,4-difluorophenyl)-2-[2-(5-methyl-1H-pyrazol-3-yl)-4-(trifluoromethyl)phenoxy]cyclopropyl]methanamine	+	Description: hALK in complex with ((1S,2S)-1-(2,4-difluorophenyl)-2-(2-(3-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenoxy)cyclopropyl)methanamine
	[[Category: Unreleased Structures]]		[[Category: Unreleased Structures]]
-	[[Category: Saikatendu, K]]
	[[Category: Zou, H]]		[[Category: Zou, H]]
-	[[Category: ~~Lane~~, W]]	+	[[Category: Saikatendu, K]]
	[[Category: Mcgrath, A.P]]		[[Category: Mcgrath, A.P]]
		+	[[Category: Lane, W]]

OCA: Protected "7jy4" [edit=sysop:move=sysop]

OCA — Wed, 09 Sep 2020 07:42:23 GMT

Protected "7jy4" [edit=sysop:move=sysop]

←Older revision

Revision as of 07:42, 9 September 2020

OCA: New page: '''Unreleased structure''' The entry 7jy4 is ON HOLD Authors: McGrath, A.P., Zou, H., Lane, W., Saikatendu, K. Description: hALK in complex with 1-[(1R,2R)-1-(2,4-difluorophenyl)-2-[2-...

OCA — Wed, 09 Sep 2020 07:42:22 GMT

New page: '''Unreleased structure''' The entry 7jy4 is ON HOLD Authors: McGrath, A.P., Zou, H., Lane, W., Saikatendu, K. Description: hALK in complex with 1-[(1R,2R)-1-(2,4-difluorophenyl)-2-[2-...

New page

'''Unreleased structure'''

The entry 7jy4 is ON HOLD

Authors: McGrath, A.P., Zou, H., Lane, W., Saikatendu, K.

Description: hALK in complex with 1-[(1R,2R)-1-(2,4-difluorophenyl)-2-[2-(5-methyl-1H-pyrazol-3-yl)-4-(trifluoromethyl)phenoxy]cyclopropyl]methanamine
[[Category: Unreleased Structures]]
[[Category: Saikatendu, K]]
[[Category: Zou, H]]
[[Category: Lane, W]]
[[Category: Mcgrath, A.P]]