8cij
From Proteopedia
(Difference between revisions)
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| - | '''Unreleased structure''' | ||
| - | + | ==CRYSTAL STRUCTURE OF HUMAN HPK1 (MAP4K1) COMPLEX WITH 2-[8-Amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-isoquinolin-3-ylamino]-6-isopropyl-5,6-dihydro-4H-1,6,8a-triaza-azulen-7-one== | |
| + | <StructureSection load='8cij' size='340' side='right'caption='[[8cij]], [[Resolution|resolution]] 2.82Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[8cij]] 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=8CIJ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8CIJ 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]] 2.821Å</td></tr> | ||
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=USF:2-[[8-azanyl-7-fluoranyl-6-(8-methyl-2,3-dihydro-1~{H}-pyrido[2,3-b][1,4]oxazin-7-yl)isoquinolin-3-yl]amino]-6-propan-2-yl-5,8-dihydro-4~{H}-pyrazolo[1,5-d][1,4]diazepin-7-one'>USF</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=8cij FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8cij OCA], [https://pdbe.org/8cij PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8cij RCSB], [https://www.ebi.ac.uk/pdbsum/8cij PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8cij ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Function == | ||
| + | [https://www.uniprot.org/uniprot/M4K1_HUMAN M4K1_HUMAN] Serine/threonine-protein kinase, which may play a role in the response to environmental stress. Appears to act upstream of the JUN N-terminal pathway. May play a role in hematopoietic lineage decisions and growth regulation. Able to autophosphorylate.<ref>PMID:24362026</ref> <ref>PMID:8824585</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Hematopoietic progenitor kinase 1 (HPK1) is regarded as a highly validated target in pre-clinical immune oncology. HPK1 has been described as regulating multiple critical signaling pathway in both adaptive and innate cells. In support of this role, HPK1 KO T cells show enhanced sensitivity to TCR activation and HPK1 KO mice display enhanced anti-tumor activity. Taken together, inhibition of HPK1 has the potential to induce enhanced anti-tumor immune response. Herein, we described the discovery of highly potent HPK1 inhibitors starting form a weak HTS hit. Using a structure-based drug design, HPK1 inhibitors exhibiting excellent cellular single-digit nanomolar potency in both proximal (pSLP76) and distal (IL-2) biomarkers along with sustained elevation of IL-2 cytokine secretion were discovered. | ||
| - | + | Discovery of quinazoline HPK1 inhibitors with high cellular potency.,Toure M, Johnson T, Li B, Schmidt R, Ma H, Neagu C, Lopez AU, Wang Y, Guler S, Xiao Y, Henkes R, Ho K, Zhang S, Chu CL, Gundra UM, Porichis F, Li L, Maurer CK, Fang Z, Musil D, DiPoto M, Friis E, Jones R, Jones C, Cummings J, Chekler E, Tanzer EM, Huck B, Sherer B Bioorg Med Chem. 2023 Jul 27;92:117423. doi: 10.1016/j.bmc.2023.117423. PMID:37531921<ref>PMID:37531921</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| - | [[Category: | + | <div class="pdbe-citations 8cij" style="background-color:#fffaf0;"></div> |
| - | [[Category: | + | == References == |
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Homo sapiens]] | ||
| + | [[Category: Large Structures]] | ||
| + | [[Category: Musil D]] | ||
| + | [[Category: Toure M]] | ||
Current revision
CRYSTAL STRUCTURE OF HUMAN HPK1 (MAP4K1) COMPLEX WITH 2-[8-Amino-7-fluoro-6-(8-methyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)-isoquinolin-3-ylamino]-6-isopropyl-5,6-dihydro-4H-1,6,8a-triaza-azulen-7-one
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