View source for 8par


==Crystal structure of human MAP4K1 with an inhibitor, BAY-405==
<StructureSection load='8par' size='340' side='right'caption='[[8par]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[8par]] 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=8PAR OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8PAR 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&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=XON:~{N}-[3,5-bis(fluoranyl)-4-[[3-[1-(trifluoromethyl)cyclopropyl]-1~{H}-pyrrolo[2,3-b]pyridin-4-yl]oxy]phenyl]-2,9-dioxa-4-azaspiro[5.5]undec-3-en-3-amine'>XON</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=8par FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8par OCA], [https://pdbe.org/8par PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8par RCSB], [https://www.ebi.ac.uk/pdbsum/8par PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8par 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> 
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== Publication Abstract from PubMed ==
Mitogen-activated protein kinase kinase kinase kinase 1 (MAP4K1) is a serine/threonine kinase that acts as an immune checkpoint downstream of T-cell receptor stimulation. MAP4K1 activity is enhanced by prostaglandin E2 (PGE2) and transforming growth factor beta (TGFbeta), immune modulators commonly present in the tumor microenvironment. Therefore, its pharmacological inhibition is an attractive immuno-oncology concept for inducing therapeutic T-cell responses in cancer patients. Here, we describe the systematic optimization of azaindole-based lead compound 1, resulting in the discovery of potent and selective MAP4K1 inhibitor 38 (BAY-405) that displays nanomolar potency in biochemical and cellular assays as well as in vivo exposure after oral dosing. BAY-405 enhances T-cell immunity and overcomes the suppressive effect of PGE2 and TGFbeta. Treatment of tumor-bearing mice shows T-cell-dependent antitumor efficacy. MAP4K1 inhibition in conjunction with PD-L1 blockade results in a superior antitumor impact, illustrating the complementarity of the single agent treatments.

Discovery of BAY-405: An Azaindole-Based MAP4K1 Inhibitor for the Enhancement of T-Cell Immunity against Cancer.,Mowat J, Carretero R, Leder G, Aiguabella Font N, Neuhaus R, Berndt S, Gunther J, Friberg A, Schafer M, Briem H, Raschke M, Miyatake Ondozabal H, Buchmann B, Boemer U, Kreft B, Hartung IV, Offringa R J Med Chem. 2024 Oct 10;67(19):17429-17453. doi: 10.1021/acs.jmedchem.4c01325. , Epub 2024 Sep 27. PMID:39331123<ref>PMID:39331123</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 8par" style="background-color:#fffaf0;"></div>
== References ==
<references/>
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Schaefer M]]