8par

From Proteopedia

(Difference between revisions)

Current revision

Crystal structure of human MAP4K1 with an inhibitor, BAY-405

Structural highlights

8par 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 2Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

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.^[1] ^[2]

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^[3]

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

References

↑ Wang H, Chen Y, Lin P, Li L, Zhou G, Liu G, Logsdon C, Jin J, Abbruzzese JL, Tan TH, Wang H. The CUL7/F-box and WD repeat domain containing 8 (CUL7/Fbxw8) ubiquitin ligase promotes degradation of hematopoietic progenitor kinase 1. J Biol Chem. 2014 Feb 14;289(7):4009-17. doi: 10.1074/jbc.M113.520106. Epub 2013 , Dec 20. PMID:24362026 doi:http://dx.doi.org/10.1074/jbc.M113.520106
↑ Hu MC, Qiu WR, Wang X, Meyer CF, Tan TH. Human HPK1, a novel human hematopoietic progenitor kinase that activates the JNK/SAPK kinase cascade. Genes Dev. 1996 Sep 15;10(18):2251-64. PMID:8824585
↑ Mowat J, Carretero R, Leder G, Aiguabella Font N, Neuhaus R, Berndt S, Günther J, Friberg A, Schäfer M, Briem H, Raschke M, Miyatake Ondozabal H, Buchmann B, Boemer U, Kreft B, Hartung IV, Offringa R. Discovery of BAY-405: An Azaindole-Based MAP4K1 Inhibitor for the Enhancement of T-Cell Immunity against Cancer. J Med Chem. 2024 Oct 10;67(19):17429-17453. PMID:39331123 doi:10.1021/acs.jmedchem.4c01325

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/8par"

Categories: Homo sapiens | Large Structures | Schaefer M

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 8par is ON HOLD  until Paper Publication
+==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>
+<div style="background-color:#fffaf0;">
+== 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.
-Authors:
+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>
-Description:
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
+<div class="pdbe-citations 8par" style="background-color:#fffaf0;"></div>
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Homo sapiens]]
+[[Category: Large Structures]]
+[[Category: Schaefer M]]

8par

From Proteopedia

Current revision

Crystal structure of human MAP4K1 with an inhibitor, BAY-405

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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