6i3u

From Proteopedia

(Difference between revisions)

Current revision

Optimization of potent and selective ATM inhibitors suitable for a proof-of-concept study in Huntington's disease models

Structural highlights

6i3u is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.09Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

PK3C3_HUMAN Catalytic subunit of the PI3K complex that mediates formation of phosphatidylinositol 3-phosphate which plays a key role in initiation and maturation of autophagosomes. Involved in the transport of lysosomal enzyme precursors to lysosomes. Required for the abcission step in cytokinesis. Required for transport from early to late endosomes.^[1] ^[2] ^[3]

Publication Abstract from PubMed

Genetic and pharmacological evidence indicates that the reduction of ataxia telangiectasia-mutated (ATM) kinase activity can ameliorate mutant huntingtin (mHTT) toxicity in cellular and animal models of Huntington's disease (HD), suggesting that selective inhibition of ATM could provide a novel clinical intervention to treat HD. Here, we describe the development and characterization of ATM inhibitor molecules to enable in vivo proof-of-concept studies in HD animal models. Starting from previously reported ATM inhibitors, we aimed with few modifications to increase brain exposure by decreasing P-glycoprotein liability while maintaining potency and selectivity. Here, we report brain-penetrant ATM inhibitors that have robust pharmacodynamic (PD) effects consistent with ATM kinase inhibition in the mouse brain and an understandable pharmacokinetic/PD (PK/PD) relationship. Compound 17 engages ATM kinase and shows robust dose-dependent inhibition of X-ray irradiation-induced KAP1 phosphorylation in the mouse brain. Furthermore, compound 17 protects against mHTT (Q73)-induced cytotoxicity in a cortical-striatal cell model of HD.

Optimization of Potent and Selective Ataxia Telangiectasia-Mutated Inhibitors Suitable for a Proof-of-Concept Study in Huntington's Disease Models.,Toledo-Sherman L, Breccia P, Cachope R, Bate JR, Angulo-Herrera I, Wishart G, Matthews KL, Martin SL, Cox HC, McAllister G, Penrose SD, Vater H, Esmieu W, Van de Poel A, Van de Bospoort R, Strijbosch A, Lamers M, Leonard P, Jarvis RE, Blackaby W, Barnes K, Eznarriaga M, Dowler S, Smith GD, Fischer DF, Lazari O, Yates D, Rose M, Jang SW, Munoz-Sanjuan I, Dominguez C J Med Chem. 2019 Mar 19. doi: 10.1021/acs.jmedchem.8b01819. PMID:30840447^[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Volinia S, Dhand R, Vanhaesebroeck B, MacDougall LK, Stein R, Zvelebil MJ, Domin J, Panaretou C, Waterfield MD. A human phosphatidylinositol 3-kinase complex related to the yeast Vps34p-Vps15p protein sorting system. EMBO J. 1995 Jul 17;14(14):3339-48. PMID:7628435
↑ Stein MP, Feng Y, Cooper KL, Welford AM, Wandinger-Ness A. Human VPS34 and p150 are Rab7 interacting partners. Traffic. 2003 Nov;4(11):754-71. PMID:14617358
↑ Sagona AP, Nezis IP, Pedersen NM, Liestol K, Poulton J, Rusten TE, Skotheim RI, Raiborg C, Stenmark H. PtdIns(3)P controls cytokinesis through KIF13A-mediated recruitment of FYVE-CENT to the midbody. Nat Cell Biol. 2010 Apr;12(4):362-71. doi: 10.1038/ncb2036. Epub 2010 Mar 7. PMID:20208530 doi:http://dx.doi.org/10.1038/ncb2036
↑ Toledo-Sherman L, Breccia P, Cachope R, Bate JR, Angulo-Herrera I, Wishart G, Matthews KL, Martin SL, Cox HC, McAllister G, Penrose SD, Vater H, Esmieu W, Van de Poel A, Van de Bospoort R, Strijbosch A, Lamers M, Leonard P, Jarvis RE, Blackaby W, Barnes K, Eznarriaga M, Dowler S, Smith GD, Fischer DF, Lazari O, Yates D, Rose M, Jang SW, Munoz-Sanjuan I, Dominguez C. Optimization of Potent and Selective Ataxia Telangiectasia-Mutated Inhibitors Suitable for a Proof-of-Concept Study in Huntington's Disease Models. J Med Chem. 2019 Mar 19. doi: 10.1021/acs.jmedchem.8b01819. PMID:30840447 doi:http://dx.doi.org/10.1021/acs.jmedchem.8b01819

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 See Also
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6i3u"

Categories: Homo sapiens | Large Structures | Leonard PM

@@ Line 3: / Line 3: @@
 <StructureSection load='6i3u' size='340' side='right'caption='[[6i3u]], [[Resolution|resolution]] 2.09&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6i3u]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6I3U OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6I3U FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6i3u]] 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=6I3U OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6I3U FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=H2E:2-morpholin-4-yl-6-[7-[(2~{R})-1-morpholin-4-ylpropan-2-yl]oxy-9~{H}-thioxanthen-4-yl]pyran-4-one'>H2E</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]] 2.09&#8491;</td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PIK3C3, VPS34 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=H2E:2-morpholin-4-yl-6-[7-[(2~{R})-1-morpholin-4-ylpropan-2-yl]oxy-9~{H}-thioxanthen-4-yl]pyran-4-one'>H2E</scene></td></tr>
-<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Phosphatidylinositol_3-kinase Phosphatidylinositol 3-kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.1.137 2.7.1.137] </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=6i3u FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6i3u OCA], [https://pdbe.org/6i3u PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6i3u RCSB], [https://www.ebi.ac.uk/pdbsum/6i3u PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6i3u ProSAT]</span></td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6i3u FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6i3u OCA], [http://pdbe.org/6i3u PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6i3u RCSB], [http://www.ebi.ac.uk/pdbsum/6i3u PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6i3u ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[http://www.uniprot.org/uniprot/PK3C3_HUMAN PK3C3_HUMAN]] Catalytic subunit of the PI3K complex that mediates formation of phosphatidylinositol 3-phosphate which plays a key role in initiation and maturation of autophagosomes. Involved in the transport of lysosomal enzyme precursors to lysosomes. Required for the abcission step in cytokinesis. Required for transport from early to late endosomes.<ref>PMID:7628435</ref> <ref>PMID:14617358</ref> <ref>PMID:20208530</ref>
+[https://www.uniprot.org/uniprot/PK3C3_HUMAN PK3C3_HUMAN] Catalytic subunit of the PI3K complex that mediates formation of phosphatidylinositol 3-phosphate which plays a key role in initiation and maturation of autophagosomes. Involved in the transport of lysosomal enzyme precursors to lysosomes. Required for the abcission step in cytokinesis. Required for transport from early to late endosomes.<ref>PMID:7628435</ref> <ref>PMID:14617358</ref> <ref>PMID:20208530</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 20: / Line 19: @@
 </div>
 <div class="pdbe-citations 6i3u" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Phosphoinositide 3-kinase 3D structures|Phosphoinositide 3-kinase 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Phosphatidylinositol 3-kinase]]
+[[Category: Leonard PM]]
-[[Category: Leonard, P M]]
-[[Category: Atm surrogate]]
-[[Category: Huntington's disease]]
-[[Category: Kinase]]
-[[Category: Lyase]]
-[[Category: Vps34]]

6i3u

From Proteopedia

Current revision

Optimization of potent and selective ATM inhibitors suitable for a proof-of-concept study in Huntington's disease models

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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