7n91

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(New page: '''Unreleased structure''' The entry 7n91 is ON HOLD Authors: Mochalkin, I. Description: P70 S6K1 IN COMPLEX WITH MSC2317067A-1 Category: Unreleased Structures [[Category: Mochalki...)
Current revision (11:13, 23 October 2024) (edit) (undo)
 
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'''Unreleased structure'''
 
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The entry 7n91 is ON HOLD
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==P70 S6K1 IN COMPLEX WITH MSC2317067A-1==
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<StructureSection load='7n91' size='340' side='right'caption='[[7n91]], [[Resolution|resolution]] 3.00&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[7n91]] 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=7N91 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7N91 FirstGlance]. <br>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1RJ:4-{[(1S)-1-(3-fluorophenyl)-2-(methylamino)ethyl]amino}quinazoline-8-carboxamide'>1RJ</scene>, <scene name='pdbligand=SEP:PHOSPHOSERINE'>SEP</scene>, <scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7n91 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7n91 OCA], [https://pdbe.org/7n91 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7n91 RCSB], [https://www.ebi.ac.uk/pdbsum/7n91 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7n91 ProSAT]</span></td></tr>
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</table>
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== Function ==
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[https://www.uniprot.org/uniprot/KS6B1_HUMAN KS6B1_HUMAN] Serine/threonine-protein kinase that acts downstream of mTOR signaling in response to growth factors and nutrients to promote cell proliferation, cell growth and cell cycle progression. Regulates protein synthesis through phosphorylation of EIF4B, RPS6 and EEF2K, and contributes to cell survival by repressing the pro-apoptotic function of BAD. Under conditions of nutrient depletion, the inactive form associates with the EIF3 translation initiation complex. Upon mitogenic stimulation, phosphorylation by the mammalian target of rapamycin complex 1 (mTORC1) leads to dissociation from the EIF3 complex and activation. The active form then phosphorylates and activates several substrates in the preinitiation complex, including the EIF2B complex and the cap-binding complex component EIF4B. Also controls translation initiation by phosphorylating a negative regulator of EIF4A, PDCD4, targeting it for ubiquitination and subsequent proteolysis. Promotes initiation of the pioneer round of protein synthesis by phosphorylating POLDIP3/SKAR. In response to IGF1, activates translation elongation by phosphorylating EEF2 kinase (EEF2K), which leads to its inhibition and thus activation of EEF2. Also plays a role in feedback regulation of mTORC2 by mTORC1 by phosphorylating RICTOR, resulting in the inhibition of mTORC2 and AKT1 signaling. Mediates cell survival by phosphorylating the pro-apoptotic protein BAD and suppressing its pro-apoptotic function. Phosphorylates mitochondrial URI1 leading to dissociation of a URI1-PPP1CC complex. The free mitochondrial PPP1CC can then dephosphorylate RPS6KB1 at 'Thr-412', which is proposed to be a negative feedback mechanism for the RPS6KB1 anti-apoptotic function. Mediates TNF-alpha-induced insulin resistance by phosphorylating IRS1 at multiple serine residues, resulting in accelerated degradation of IRS1. In cells lacking functional TSC1-2 complex, constitutively phosphorylates and inhibits GSK3B. May be involved in cytoskeletal rearrangement through binding to neurabin.<ref>PMID:11500364</ref> <ref>PMID:12801526</ref> <ref>PMID:15341740</ref> <ref>PMID:15071500</ref> <ref>PMID:14673156</ref> <ref>PMID:16286006</ref> <ref>PMID:17052453</ref> <ref>PMID:17053147</ref> <ref>PMID:17936702</ref> <ref>PMID:18952604</ref> <ref>PMID:19085255</ref> <ref>PMID:19720745</ref> <ref>PMID:19995915</ref> <ref>PMID:19935711</ref>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Herein, we report the discovery of a novel class of quinazoline carboxamides as dual p70S6k/Akt inhibitors for the treatment of tumors driven by alterations to the PI3K/Akt/mTOR (PAM) pathway. Through the screening of in-house proprietary kinase library, 4-benzylamino-quinazoline-8-carboxylic acid amide 1 stood out, with sub-micromolar p70S6k biochemical activity, as the starting point for a structurally enabled p70S6K/Akt dual inhibitor program that led to the discovery of M2698, a dual p70S6k/Akt inhibitor. M2698 is kinase selective, possesses favorable physical, chemical, and DMPK profiles, is orally available and well tolerated, and displayed tumor control in multiple in vivo studies of PAM pathway-driven tumors.
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Authors: Mochalkin, I.
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Identification of Clinical Candidate M2698, a Dual p70S6K and Akt Inhibitor, for Treatment of PAM Pathway-Altered Cancers.,DeSelm L, Huck B, Lan R, Neagu C, Potnick J, Xiao Y, Chen X, Jones R, Richardson TE, Heasley BH, Haxell T, Moore J, Tian H, Georgi K, Rohdich F, Sutton A, Johnson T, Mochalkin I, Jackson J, Lin J, Crowley L, Machl A, Clark A, Wilker E, Sherer B, Goutopoulos A J Med Chem. 2021 Oct 14;64(19):14603-14619. doi: 10.1021/acs.jmedchem.1c01087. , Epub 2021 Oct 1. PMID:34596404<ref>PMID:34596404</ref>
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Description: P70 S6K1 IN COMPLEX WITH MSC2317067A-1
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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[[Category: Unreleased Structures]]
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</div>
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[[Category: Mochalkin, I]]
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<div class="pdbe-citations 7n91" style="background-color:#fffaf0;"></div>
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==See Also==
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*[[Ribosomal protein S6 kinase 3D structures|Ribosomal protein S6 kinase 3D structures]]
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== References ==
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<references/>
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__TOC__
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</StructureSection>
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[[Category: Homo sapiens]]
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[[Category: Large Structures]]
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[[Category: Mochalkin I]]

Current revision

P70 S6K1 IN COMPLEX WITH MSC2317067A-1

PDB ID 7n91

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