OCA at 06:00, 11 October 2023

OCA — Wed, 11 Oct 2023 06:00:57 GMT

←Older revision		Revision as of 06:00, 11 October 2023
Line 1:		Line 1:
-	'''Unreleased structure'''

-	The entry ~~8t6g~~ is ~~ON HOLD until Paper~~ Publication	+	==Identification of GDC-1971 (RLY-1971), a SHP2 inhibitor designed for the treatment of solid tumors==
		+	<StructureSection load='8t6g' size='340' side='right'caption='[[8t6g]], [[Resolution\|resolution]] 1.84Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[8t6g]] 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=8T6G OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8T6G 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]] 1.84Å</td></tr>
		+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=YT2:(1S)-1-{6-[(1S)-1-amino-1,3-dihydrospiro[indene-2,4-piperidin]-1-yl]-3-(3,4-dihydro-1,5-naphthyridin-1(2H)-yl)-1H-pyrazolo[3,4-b]pyrazin-5-yl}ethan-1-ol'>YT2</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=8t6g FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8t6g OCA], [https://pdbe.org/8t6g PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8t6g RCSB], [https://www.ebi.ac.uk/pdbsum/8t6g PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8t6g ProSAT]</span></td></tr>
		+	</table>
		+	== Disease ==
		+	[https://www.uniprot.org/uniprot/PTN11_HUMAN PTN11_HUMAN] Defects in PTPN11 are the cause of LEOPARD syndrome type 1 (LEOPARD1) [MIM:[https://omim.org/entry/151100 151100]. It is an autosomal dominant disorder allelic with Noonan syndrome. The acronym LEOPARD stands for lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonic stenosis, abnormalities of genitalia, retardation of growth, and deafness.<ref>PMID:12058348</ref> <ref>PMID:14961557</ref> <ref>PMID:15389709</ref> <ref>PMID:15520399</ref> <ref>PMID:15121796</ref> <ref>PMID:15690106</ref> <ref>PMID:16679933</ref> Defects in PTPN11 are the cause of Noonan syndrome type 1 (NS1) [MIM:[https://omim.org/entry/163950 163950]. Noonan syndrome (NS) is a disorder characterized by dysmorphic facial features, short stature, hypertelorism, cardiac anomalies, deafness, motor delay, and a bleeding diathesis. Some patients with Noonan syndrome type 1 develop multiple giant cell lesions of the jaw or other bony or soft tissues, which are classified as pigmented villomoduolar synovitis (PVNS) when occurring in the jaw or joints. Note=Mutations in PTPN11 account for more than 50% of the cases. Rarely, NS is associated with juvenile myelomonocytic leukemia (JMML). NS1 inheritance is autosomal dominant.<ref>PMID:11704759</ref> <ref>PMID:11992261</ref> <ref>PMID:12325025</ref> <ref>PMID:12161469</ref> <ref>PMID:12529711</ref> <ref>PMID:12634870</ref> <ref>PMID:12739139</ref> <ref>PMID:12960218</ref> <ref>PMID:12717436</ref> <ref>PMID:15384080</ref> <ref>PMID:15948193</ref> <ref>PMID:19020799</ref> Defects in PTPN11 are a cause of juvenile myelomonocytic leukemia (JMML) [MIM:[https://omim.org/entry/607785 607785]. JMML is a pediatric myelodysplastic syndrome that constitutes approximately 30% of childhood cases of myelodysplastic syndrome (MDS) and 2% of leukemia. It is characterized by leukocytosis with tissue infiltration and in vitro hypersensitivity of myeloid progenitors to granulocyte-macrophage colony stimulating factor.<ref>PMID:12717436</ref> Defects in PTPN11 are a cause of metachondromatosis (MC) [MIM:[https://omim.org/entry/156250 156250]. It is a skeletal disorder with radiologic fetarures of both multiple exostoses and Ollier disease, characterized by the presence of multiple enchondromas and osteochondroma-like lesions.<ref>PMID:20577567</ref>
		+	== Function ==
		+	[https://www.uniprot.org/uniprot/PTN11_HUMAN PTN11_HUMAN] Acts downstream of various receptor and cytoplasmic protein tyrosine kinases to participate in the signal transduction from the cell surface to the nucleus. Dephosphorylates ROCK2 at Tyr-722 resulting in stimulatation of its RhoA binding activity.<ref>PMID:10655584</ref> <ref>PMID:18829466</ref> <ref>PMID:18559669</ref>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	Protein tyrosine phosphatase SHP2 mediates RAS-driven MAPK signaling and has emerged in recent years as a target of interest in oncology, both for treating with a single agent and in combination with a KRAS inhibitor. We were drawn to the pharmacological potential of SHP2 inhibition, especially following the initial observation that drug-like compounds could bind an allosteric site and enforce a closed, inactive state of the enzyme. Here, we describe the identification and characterization of GDC-1971 (formerly RLY-1971), a SHP2 inhibitor currently in clinical trials in combination with KRAS G12C inhibitor divarasib (GDC-6036) for the treatment of solid tumors driven by a KRAS G12C mutation.

-	~~Authors: Tang~~, Y., ~~Nugyen~~, V., Wilbur, J.D.	+	Identification of GDC-1971 (RLY-1971), a SHP2 Inhibitor Designed for the Treatment of Solid Tumors.,Taylor AM, Williams BR, Giordanetto F, Kelley EH, Lescarbeau A, Shortsleeves K, Tang Y, Walters WP, Arrazate A, Bowman C, Brophy E, Chan EW, Deshmukh G, Greisman JB, Hunsaker TL, Kipp DR, Saenz Lopez-Larrocha P, Maddalo D, Martin IJ, Maragakis P, Merchant M, Murcko M, Nisonoff H, Nguyen V, Nguyen V, Orozco O, Owen C, Pierce L, Schmidt M, Shaw DE, Smith S, Therrien E, Tran JC, Watters J, Waters NJ, Wilbur J, Willmore L J Med Chem. 2023 Sep 29. doi: 10.1021/acs.jmedchem.3c00483. PMID:37774359<ref>PMID:37774359</ref>

-	~~Description: Identification of GDC-1971 (RLY-1971)~~, a ~~SHP2 inhibitor designed for~~ the ~~treatment~~ of ~~solid tumors~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	[[Category: ~~Unreleased~~ Structures]]	+	</div>
-	[[Category: ~~Tang, Y~~]]	+	<div class="pdbe-citations 8t6g" style="background-color:#fffaf0;"></div>
-	[[Category: ~~Wilbur, J.D~~]]	+	== References ==
-	[[Category: ~~Nugyen, V~~]]	+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Homo sapiens]]
		+	[[Category: Large Structures]]
		+	[[Category: Nugyen V]]
		+	[[Category: Tang Y]]
		+	[[Category: Wilbur JD]]

OCA at 11:09, 26 July 2023

OCA — Wed, 26 Jul 2023 11:09:05 GMT

←Older revision		Revision as of 11:09, 26 July 2023
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 8t6g is ON HOLD	+	The entry 8t6g is ON HOLD until Paper Publication

	Authors: Tang, Y., Nugyen, V., Wilbur, J.D.		Authors: Tang, Y., Nugyen, V., Wilbur, J.D.
Line 7:		Line 7:
	Description: Identification of GDC-1971 (RLY-1971), a SHP2 inhibitor designed for the treatment of solid tumors		Description: Identification of GDC-1971 (RLY-1971), a SHP2 inhibitor designed for the treatment of solid tumors
	[[Category: Unreleased Structures]]		[[Category: Unreleased Structures]]
-	[[Category: Wilbur, J.D]]
	[[Category: Tang, Y]]		[[Category: Tang, Y]]
		+	[[Category: Wilbur, J.D]]
	[[Category: Nugyen, V]]		[[Category: Nugyen, V]]

OCA: Protected "8t6g" [edit=sysop:move=sysop]

OCA — Wed, 21 Jun 2023 08:34:06 GMT

Protected "8t6g" [edit=sysop:move=sysop]

←Older revision

Revision as of 08:34, 21 June 2023

OCA: New page: '''Unreleased structure''' The entry 8t6g is ON HOLD Authors: Tang, Y., Nugyen, V., Wilbur, J.D. Description: Identification of GDC-1971 (RLY-1971), a SHP2 inhibitor designed for the t...

OCA — Wed, 21 Jun 2023 08:34:05 GMT

New page: '''Unreleased structure''' The entry 8t6g is ON HOLD Authors: Tang, Y., Nugyen, V., Wilbur, J.D. Description: Identification of GDC-1971 (RLY-1971), a SHP2 inhibitor designed for the t...

New page

'''Unreleased structure'''

The entry 8t6g is ON HOLD

Authors: Tang, Y., Nugyen, V., Wilbur, J.D.

Description: Identification of GDC-1971 (RLY-1971), a SHP2 inhibitor designed for the treatment of solid tumors
[[Category: Unreleased Structures]]
[[Category: Wilbur, J.D]]
[[Category: Tang, Y]]
[[Category: Nugyen, V]]

8t6g - Revision history

OCA at 06:00, 11 October 2023

OCA at 11:09, 26 July 2023

OCA: Protected "8t6g" [edit=sysop:move=sysop]

OCA: New page: '''Unreleased structure''' The entry 8t6g is ON HOLD Authors: Tang, Y., Nugyen, V., Wilbur, J.D. Description: Identification of GDC-1971 (RLY-1971), a SHP2 inhibitor designed for the t...