7rt2 - Revision history

OCA at 15:01, 6 March 2024

2024-03-06T15:01:54Z

← Older revision		Revision as of 15:01, 6 March 2024
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	== Function ==		== Function ==
	[https://www.uniprot.org/uniprot/RASK_HUMAN RASK_HUMAN] Ras proteins bind GDP/GTP and possess intrinsic GTPase activity.		[https://www.uniprot.org/uniprot/RASK_HUMAN RASK_HUMAN] Ras proteins bind GDP/GTP and possess intrinsic GTPase activity.
	~~<div style="background-color:#fffaf0;">~~
	~~== Publication Abstract from PubMed ==~~
	KRAS(G12D), the most common oncogenic KRAS mutation, is a promising target for the treatment of solid tumors. However, when compared to KRAS(G12C), selective inhibition of KRAS(G12D) presents a significant challenge due to the requirement of inhibitors to bind KRAS(G12D) with high enough affinity to obviate the need for covalent interactions with the mutant KRAS protein. Here, we report the discovery and characterization of the first noncovalent, potent, and selective KRAS(G12D) inhibitor, MRTX1133, which was discovered through an extensive structure-based activity improvement and shown to be efficacious in a KRAS(G12D) mutant xenograft mouse tumor model.

	Identification of MRTX1133, a Noncovalent, Potent, and Selective KRAS(G12D) Inhibitor.,Wang X, Allen S, Blake JF, Bowcut V, Briere DM, Calinisan A, Dahlke JR, Fell JB, Fischer JP, Gunn RJ, Hallin J, Laguer J, Lawson JD, Medwid J, Newhouse B, Nguyen P, O'Leary JM, Olson P, Pajk S, Rahbaek L, Rodriguez M, Smith CR, Tang TP, Thomas NC, Vanderpool D, Vigers GP, Christensen JG, Marx MA J Med Chem. 2021 Dec 10. doi: 10.1021/acs.jmedchem.1c01688. PMID:34889605<ref>PMID:34889605</ref>

	~~From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>~~
	~~</div>~~
	~~<div class="pdbe-citations 7rt2" style="background-color:#fffaf0;"></div>~~

	==See Also==		==See Also==

OCA at 16:38, 18 October 2023

2023-10-18T16:38:12Z

← Older revision		Revision as of 16:38, 18 October 2023
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	<StructureSection load='7rt2' size='340' side='right'caption='[[7rt2]], [[Resolution\|resolution]] 1.59Å' scene=''>		<StructureSection load='7rt2' size='340' side='right'caption='[[7rt2]], [[Resolution\|resolution]] 1.59Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[7rt2]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7RT2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7RT2 FirstGlance]. <br>		<table><tr><td colspan='2'>[[7rt2]] 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=7RT2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7RT2 FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=7NL:4-(4-[(1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-{[(2R,4R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol'>7NL</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=GDP:GUANOSINE-5-DIPHOSPHATE'>GDP</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</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]] 1.59Å</td></tr>
	~~<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[7rpz\|7rpz]]</div></td></tr>~~		<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=7NL:4-(4-[(1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-{[(2R,4R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol'>7NL</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=GDP:GUANOSINE-5-DIPHOSPHATE'>GDP</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr>
	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Small_monomeric_GTPase Small monomeric GTPase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.6.5.2 3.6.5.2] </span></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=7rt2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7rt2 OCA], [https://pdbe.org/7rt2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7rt2 RCSB], [https://www.ebi.ac.uk/pdbsum/7rt2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7rt2 ProSAT]</span></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=7rt2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7rt2 OCA], [https://pdbe.org/7rt2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7rt2 RCSB], [https://www.ebi.ac.uk/pdbsum/7rt2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7rt2 ProSAT]</span></td></tr>
	</table>		</table>
			== Disease ==
			[https://www.uniprot.org/uniprot/RASK_HUMAN RASK_HUMAN] Defects in KRAS are a cause of acute myelogenous leukemia (AML) [MIM:[https://omim.org/entry/601626 601626]. AML is a malignant disease in which hematopoietic precursors are arrested in an early stage of development.<ref>PMID:8955068</ref> Defects in KRAS 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. Defects in KRAS are the cause of Noonan syndrome type 3 (NS3) [MIM:[https://omim.org/entry/609942 609942]. Noonan syndrome (NS) [MIM:[https://omim.org/entry/163950 163950] is a disorder characterized by dysmorphic facial features, short stature, hypertelorism, cardiac anomalies, deafness, motor delay, and a bleeding diathesis. It is a genetically heterogeneous and relatively common syndrome, with an estimated incidence of 1 in 1000-2500 live births. Rarely, NS is associated with juvenile myelomonocytic leukemia (JMML). NS3 inheritance is autosomal dominant.<ref>PMID:16773572</ref> <ref>PMID:16474405</ref> <ref>PMID:17468812</ref> <ref>PMID:17056636</ref> <ref>PMID:19396835</ref> <ref>PMID:20949621</ref> Defects in KRAS are a cause of gastric cancer (GASC) [MIM:[https://omim.org/entry/613659 613659]; also called gastric cancer intestinal or stomach cancer. Gastric cancer is a malignant disease which starts in the stomach, can spread to the esophagus or the small intestine, and can extend through the stomach wall to nearby lymph nodes and organs. It also can metastasize to other parts of the body. The term gastric cancer or gastric carcinoma refers to adenocarcinoma of the stomach that accounts for most of all gastric malignant tumors. Two main histologic types are recognized, diffuse type and intestinal type carcinomas. Diffuse tumors are poorly differentiated infiltrating lesions, resulting in thickening of the stomach. In contrast, intestinal tumors are usually exophytic, often ulcerating, and associated with intestinal metaplasia of the stomach, most often observed in sporadic disease.<ref>PMID:3034404</ref> <ref>PMID:7773929</ref> <ref>PMID:14534542</ref> Note=Defects in KRAS are a cause of pylocytic astrocytoma (PA). Pylocytic astrocytomas are neoplasms of the brain and spinal cord derived from glial cells which vary from histologically benign forms to highly anaplastic and malignant tumors.<ref>PMID:8439212</ref> Defects in KRAS are a cause of cardiofaciocutaneous syndrome (CFC syndrome) [MIM:[https://omim.org/entry/115150 115150]; also known as cardio-facio-cutaneous syndrome. CFC syndrome is characterized by a distinctive facial appearance, heart defects and mental retardation. Heart defects include pulmonic stenosis, atrial septal defects and hypertrophic cardiomyopathy. Some affected individuals present with ectodermal abnormalities such as sparse, friable hair, hyperkeratotic skin lesions and a generalized ichthyosis-like condition. Typical facial features are similar to Noonan syndrome. They include high forehead with bitemporal constriction, hypoplastic supraorbital ridges, downslanting palpebral fissures, a depressed nasal bridge, and posteriorly angulated ears with prominent helices. The inheritance of CFC syndrome is autosomal dominant. Note=KRAS mutations are involved in cancer development.
			== Function ==
			[https://www.uniprot.org/uniprot/RASK_HUMAN RASK_HUMAN] Ras proteins bind GDP/GTP and possess intrinsic GTPase activity.
	<div style="background-color:#fffaf0;">		<div style="background-color:#fffaf0;">
	== Publication Abstract from PubMed ==		== Publication Abstract from PubMed ==
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	</div>		</div>
	<div class="pdbe-citations 7rt2" style="background-color:#fffaf0;"></div>		<div class="pdbe-citations 7rt2" style="background-color:#fffaf0;"></div>

			==See Also==
			*[[GTPase KRas 3D structures\|GTPase KRas 3D structures]]
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
			[[Category: Homo sapiens]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
	~~[[Category: Small monomeric GTPase]]~~		[[Category: Gunn RG]]
	[[Category: Gunn~~, R G~~]]		[[Category: Lawson JD]]
	[[Category: Lawson~~, J D~~]]		[[Category: Marx MA]]
	[[Category: Marx~~, M A~~]]		[[Category: Thomas NC]]
	[[Category: Thomas~~, N C~~]]		[[Category: Xiaolun W]]
	[[Category: Xiaolun, W]]
	~~[[Category: G12d]]~~
	~~[[Category: Gtpase]]~~
	~~[[Category: Hydrolase-inhibitor complex]]~~
	~~[[Category: Kra]]~~
	~~[[Category: Kras4b]]~~
	~~[[Category: Mrtx-1133]]~~
	~~[[Category: Oncology]]~~
	~~[[Category: Oncoprotein~~]]

OCA at 07:26, 9 March 2022

2022-03-09T07:26:13Z

← Older revision		Revision as of 07:26, 9 March 2022
Line 1:		Line 1:

	==Crystal Structure of KRAS G12D with compound 25 (4-(4-[(1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-{[(2R,4R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol) bound==		==Crystal Structure of KRAS G12D with compound 25 (4-(4-[(1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-{[(2R,4R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol) bound==
	<StructureSection load='7rt2' size='340' side='right'caption='[[7rt2]]' scene=''>		<StructureSection load='7rt2' size='340' side='right'caption='[[7rt2]], [[Resolution\|resolution]] 1.59Å' 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=7RT2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7RT2 FirstGlance]. <br>		<table><tr><td colspan='2'>[[7rt2]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7RT2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7RT2 FirstGlance]. <br>
	</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=7rt2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7rt2 OCA], [https://pdbe.org/7rt2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7rt2 RCSB], [https://www.ebi.ac.uk/pdbsum/7rt2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7rt2 ProSAT]</span></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=7NL:4-(4-[(1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-{[(2R,4R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol'>7NL</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=GDP:GUANOSINE-5-DIPHOSPHATE'>GDP</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr>
			<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[7rpz\|7rpz]]</div></td></tr>
			<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Small_monomeric_GTPase Small monomeric GTPase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.6.5.2 3.6.5.2] </span></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=7rt2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7rt2 OCA], [https://pdbe.org/7rt2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7rt2 RCSB], [https://www.ebi.ac.uk/pdbsum/7rt2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7rt2 ProSAT]</span></td></tr>
	</table>		</table>
			<div style="background-color:#fffaf0;">
			== Publication Abstract from PubMed ==
			KRAS(G12D), the most common oncogenic KRAS mutation, is a promising target for the treatment of solid tumors. However, when compared to KRAS(G12C), selective inhibition of KRAS(G12D) presents a significant challenge due to the requirement of inhibitors to bind KRAS(G12D) with high enough affinity to obviate the need for covalent interactions with the mutant KRAS protein. Here, we report the discovery and characterization of the first noncovalent, potent, and selective KRAS(G12D) inhibitor, MRTX1133, which was discovered through an extensive structure-based activity improvement and shown to be efficacious in a KRAS(G12D) mutant xenograft mouse tumor model.

			Identification of MRTX1133, a Noncovalent, Potent, and Selective KRAS(G12D) Inhibitor.,Wang X, Allen S, Blake JF, Bowcut V, Briere DM, Calinisan A, Dahlke JR, Fell JB, Fischer JP, Gunn RJ, Hallin J, Laguer J, Lawson JD, Medwid J, Newhouse B, Nguyen P, O'Leary JM, Olson P, Pajk S, Rahbaek L, Rodriguez M, Smith CR, Tang TP, Thomas NC, Vanderpool D, Vigers GP, Christensen JG, Marx MA J Med Chem. 2021 Dec 10. doi: 10.1021/acs.jmedchem.1c01688. PMID:34889605<ref>PMID:34889605</ref>

			From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
			</div>
			<div class="pdbe-citations 7rt2" style="background-color:#fffaf0;"></div>
			== References ==
			<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
	[[Category: Large Structures]]		[[Category: Large Structures]]
	[[Category: Gunn RG]]		[[Category: Small monomeric GTPase]]
	[[Category: Lawson JD]]		[[Category: Gunn, R G]]
	[[Category: Marx MA]]		[[Category: Lawson, J D]]
	[[Category: Thomas NC]]		[[Category: Marx, M A]]
	[[Category: Xiaolun W]]		[[Category: Thomas, N C]]
			[[Category: Xiaolun, W]]
			[[Category: G12d]]
			[[Category: Gtpase]]
			[[Category: Hydrolase-inhibitor complex]]
			[[Category: Kra]]
			[[Category: Kras4b]]
			[[Category: Mrtx-1133]]
			[[Category: Oncology]]
			[[Category: Oncoprotein]]

OCA at 15:28, 22 December 2021

2021-12-22T15:28:58Z

← Older revision		Revision as of 15:28, 22 December 2021
Line 1:		Line 1:
	~~'''Unreleased structure'''~~

	~~The entry~~ 7rt2 is ~~ON HOLD until Paper Publication~~		==Crystal Structure of KRAS G12D with compound 25 (4-(4-[(1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl]-8-fluoro-2-{[(2R,4R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}pyrido[4,3-d]pyrimidin-7-yl)naphthalen-2-ol) bound==
			<StructureSection load='7rt2' size='340' side='right'caption='[[7rt2]]' scene=''>
	~~Authors~~:		== Structural highlights ==
			<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7RT2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7RT2 FirstGlance]. <br>
	~~Description~~:		</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=7rt2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7rt2 OCA], [https://pdbe.org/7rt2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7rt2 RCSB], [https://www.ebi.ac.uk/pdbsum/7rt2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7rt2 ProSAT]</span></td></tr>
	[[Category: ~~Unreleased Structures~~]]		</table>
			__TOC__
			</StructureSection>
			[[Category: Large Structures]]
			[[Category: Gunn RG]]
			[[Category: Lawson JD]]
			[[Category: Marx MA]]
			[[Category: Thomas NC]]
			[[Category: Xiaolun W]]

OCA at 08:15, 15 September 2021

2021-09-15T08:15:36Z

← Older revision		Revision as of 08:15, 15 September 2021
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	'''Unreleased structure'''		'''Unreleased structure'''

	The entry 7rt2 is ON HOLD		The entry 7rt2 is ON HOLD until Paper Publication

	Authors:		Authors:

OCA: Protected "7rt2" [edit=sysop:move=sysop]

2021-08-18T05:12:21Z

Protected "7rt2" [edit=sysop:move=sysop]

← Older revision	Revision as of 05:12, 18 August 2021
(No difference)

OCA: New page: '''Unreleased structure''' The entry 7rt2 is ON HOLD Authors: Description: Category: Unreleased Structures

2021-08-18T05:12:20Z

New page: '''Unreleased structure''' The entry 7rt2 is ON HOLD Authors: Description: Category: Unreleased Structures

New page

'''Unreleased structure'''

The entry 7rt2 is ON HOLD

Authors:

Description:
[[Category: Unreleased Structures]]