OCA at 09:10, 28 December 2022

OCA — Wed, 28 Dec 2022 09:10:57 GMT

←Older revision		Revision as of 09:10, 28 December 2022
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-	'''Unreleased structure'''

-	~~The entry~~ 8era is ~~ON HOLD~~	+	==RMC-5552 in complex with mTORC1 and FKBP12==
		+	<StructureSection load='8era' size='340' side='right'caption='[[8era]], [[Resolution\|resolution]] 2.86Å' scene=''>
		+	== Structural highlights ==
		+	<table><tr><td colspan='2'>[[8era]] is a 4 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=8ERA OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8ERA FirstGlance]. <br>
		+	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=XYU:(3S,5R,6R,7E,9R,10R,12R,14S,15E,17E,19E,21S,23S,26R,27R,30R,34aS)-5,9,27-trihydroxy-3-{(2R)-1-[(1S,3R,4R)-4-hydroxy-3-methoxycyclohexyl]propan-2-yl}-10,21-dimethoxy-6,8,12,14,20,26-hexamethyl-5,6,9,10,12,13,14,21,22,23,24,25,26,27,32,33,34,34a-octadecahydro-3H-23,27-epoxypyrido[2,1-c][1,4]oxazacyclohentriacontine-1,11,28,29(4H,31H)-tetrone'>XYU</scene>, <scene name='pdbligand=XZ9:1-[6-{[(3M)-4-amino-3-(2-amino-1,3-benzoxazol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl}-3,4-dihydroisoquinolin-2(1H)-yl]-3-hydroxypropan-1-one'>XZ9</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=8era FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8era OCA], [https://pdbe.org/8era PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8era RCSB], [https://www.ebi.ac.uk/pdbsum/8era PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8era ProSAT]</span></td></tr>
		+	</table>
		+	== Function ==
		+	[https://www.uniprot.org/uniprot/MTOR_HUMAN MTOR_HUMAN] Serine/threonine protein kinase which is a central regulator of cellular metabolism, growth and survival in response to hormones, growth factors, nutrients, energy and stress signals. Functions as part of 2 structurally and functionally distinct signaling complexes mTORC1 and mTORC2 (mTOR complex 1 and 2). Activated mTORC1 up-regulates protein synthesis by phosphorylating key regulators of mRNA translation and ribosome synthesis. This includes phosphorylation of EIF4EBP1 and release of its inhibition toward the elongation initiation factor 4E (eiF4E). Moreover, phosphorylates and activates RPS6KB1 and RPS6KB2 that promote protein synthesis by modulating the activity of their downstream targets including ribosomal protein S6, eukaryotic translation initiation factor EIF4B and the inhibitor of translation initiation PDCD4. Regulates ribosome synthesis by activating RNA polymerase III-dependent transcription through phosphorylation and inhibition of MAF1 a RNA polymerase III-repressor. In parallel to protein synthesis, also regulates lipid synthesis through SREBF1/SREBP1 and LPIN1. To maintain energy homeostasis mTORC1 may also regulate mitochondrial biogenesis through regulation of PPARGC1A. mTORC1 also negatively regulates autophagy through phosphorylation of ULK1. Under nutrient sufficiency, phosphorylates ULK1 at 'Ser-758', disrupting the interaction with AMPK and preventing activation of ULK1. Also prevents autophagy through phosphorylation of the autophagy inhibitor DAP. mTORC1 exerts a feedback control on upstream growth factor signaling that includes phosphorylation and activation of GRB10 a INSR-dependent signaling suppressor. Among other potential targets mTORC1 may phosphorylate CLIP1 and regulate microtubules. As part of the mTORC2 complex MTOR may regulate other cellular processes including survival and organization of the cytoskeleton. Plays a critical role in the phosphorylation at 'Ser-473' of AKT1, a pro-survival effector of phosphoinositide 3-kinase, facilitating its activation by PDK1. mTORC2 may regulate the actin cytoskeleton, through phosphorylation of PRKCA, PXN and activation of the Rho-type guanine nucleotide exchange factors RHOA and RAC1A or RAC1B. mTORC2 also regulates the phosphorylation of SGK1 at 'Ser-422'.<ref>PMID:12150925</ref> <ref>PMID:12150926</ref> <ref>PMID:12231510</ref> <ref>PMID:12087098</ref> <ref>PMID:14651849</ref> <ref>PMID:12718876</ref> <ref>PMID:15268862</ref> <ref>PMID:15545625</ref> <ref>PMID:15467718</ref> <ref>PMID:15718470</ref> <ref>PMID:18925875</ref> <ref>PMID:18762023</ref> <ref>PMID:18497260</ref> <ref>PMID:20537536</ref> <ref>PMID:20516213</ref> <ref>PMID:21659604</ref>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	Hyperactivation of mTOR kinase by mutations in the PI3K/mTOR pathway or by crosstalk with other mutant cancer drivers, such as RAS, is a feature of many tumors. Multiple allosteric inhibitors of mTORC1 and orthosteric dual inhibitors of mTORC1 and mTORC2 have been developed as anticancer drugs, but their clinical utility has been limited. To address these limitations, we have developed a novel class of "bi-steric inhibitors" that interact with both the orthosteric and the allosteric binding sites in order to deepen the inhibition of mTORC1 while also preserving selectivity for mTORC1 over mTORC2. In this report, we describe the discovery and preclinical profile of the development candidate RMC-5552 and the in vivo preclinical tool compound RMC-6272. We also present evidence that selective inhibition of mTORC1 in combination with covalent inhibition of KRAS(G12C) shows increased antitumor activity in a preclinical model of KRAS(G12C) mutant NSCLC that exhibits resistance to KRAS(G12C) inhibitor monotherapy.

-	~~Authors: Tomlinson~~, ~~A.C~~.A., ~~Yano~~, J.K.	+	Discovery of RMC-5552, a Selective Bi-Steric Inhibitor of mTORC1, for the Treatment of mTORC1-Activated Tumors.,Burnett GL, Yang YC, Aggen JB, Pitzen J, Gliedt MK, Semko CM, Marquez A, Evans JW, Wang G, Won WS, Tomlinson ACA, Kiss G, Tzitzilonis C, Thottumkara AP, Cregg J, Mellem KT, Choi JS, Lee JC, Zhao Y, Lee BJ, Meyerowitz JG, Knox JE, Jiang J, Wang Z, Wildes D, Wang Z, Singh M, Smith JAM, Gill AL J Med Chem. 2022 Dec 19. doi: 10.1021/acs.jmedchem.2c01658. PMID:36533617<ref>PMID:36533617</ref>

-	~~Description: RMC~~-~~5552 in complex with mTORC1 and FKBP12~~	+	From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
-	[[Category: ~~Unreleased~~ Structures]]	+	</div>
-	[[Category: Tomlinson~~, A.C.A~~]]	+	<div class="pdbe-citations 8era" style="background-color:#fffaf0;"></div>
-	[[Category: Yano~~, J.K~~]]	+	== References ==
		+	<references/>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Homo sapiens]]
		+	[[Category: Large Structures]]
		+	[[Category: Tomlinson ACA]]
		+	[[Category: Yano JK]]

OCA at 06:22, 21 December 2022

OCA — Wed, 21 Dec 2022 06:22:39 GMT

←Older revision		Revision as of 06:22, 21 December 2022
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	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 8era is ON HOLD ~~until sometime in the future~~	+	The entry 8era is ON HOLD

	Authors: Tomlinson, A.C.A., Yano, J.K.		Authors: Tomlinson, A.C.A., Yano, J.K.

-	Description: ~~FKBP12~~-~~FRB~~ in ~~Complex~~ with ~~Compound 11~~	+	Description: RMC-5552 in complex with mTORC1 and FKBP12
	[[Category: Unreleased Structures]]		[[Category: Unreleased Structures]]
	[[Category: Tomlinson, A.C.A]]		[[Category: Tomlinson, A.C.A]]
	[[Category: Yano, J.K]]		[[Category: Yano, J.K]]

OCA at 04:00, 26 October 2022

OCA — Wed, 26 Oct 2022 04:00:33 GMT

←Older revision		Revision as of 04:00, 26 October 2022
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 8era is ON HOLD	+	The entry 8era is ON HOLD until sometime in the future

	Authors: Tomlinson, A.C.A., Yano, J.K.		Authors: Tomlinson, A.C.A., Yano, J.K.

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

OCA — Wed, 19 Oct 2022 17:28:49 GMT

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

←Older revision

Revision as of 17:28, 19 October 2022

OCA: New page: '''Unreleased structure''' The entry 8era is ON HOLD Authors: Tomlinson, A.C.A., Yano, J.K. Description: FKBP12-FRB in Complex with Compound 11 Category: Unreleased Structures [[Ca...

OCA — Wed, 19 Oct 2022 17:28:46 GMT

New page: '''Unreleased structure''' The entry 8era is ON HOLD Authors: Tomlinson, A.C.A., Yano, J.K. Description: FKBP12-FRB in Complex with Compound 11 Category: Unreleased Structures [[Ca...

New page

'''Unreleased structure'''

The entry 8era is ON HOLD

Authors: Tomlinson, A.C.A., Yano, J.K.

Description: FKBP12-FRB in Complex with Compound 11
[[Category: Unreleased Structures]]
[[Category: Tomlinson, A.C.A]]
[[Category: Yano, J.K]]

8era - Revision history

OCA at 09:10, 28 December 2022

OCA at 06:22, 21 December 2022

OCA at 04:00, 26 October 2022

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

OCA: New page: '''Unreleased structure''' The entry 8era is ON HOLD Authors: Tomlinson, A.C.A., Yano, J.K. Description: FKBP12-FRB in Complex with Compound 11 Category: Unreleased Structures [[Ca...