5tt7 - Revision history

OCA at 14:23, 6 March 2024

OCA — Wed, 06 Mar 2024 14:23:09 GMT

←Older revision		Revision as of 14:23, 6 March 2024
Line 1:		Line 1:

	==Discovery of TAK-659, an Orally Available Investigational Inhibitor of Spleen Tyrosine Kinase (SYK)==		==Discovery of TAK-659, an Orally Available Investigational Inhibitor of Spleen Tyrosine Kinase (SYK)==
-	<StructureSection load='5tt7' size='340' side='right' caption='[[5tt7]], [[Resolution\|resolution]] 1.77Å' scene=''>	+	<StructureSection load='5tt7' size='340' side='right'caption='[[5tt7]], [[Resolution\|resolution]] 1.77Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[5tt7]] 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=5TT7 OCA]. For a <b>guided tour on the structure components</b> use [~~http~~://~~oca~~.~~weizmann.ac.il/oca-docs~~/fgij/fg.htm?mol=5TT7 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[5tt7]] 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=5TT7 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5TT7 FirstGlance]. <br>
-	</td></tr><tr id='~~ligand~~'><td class="sblockLbl"><b>[[~~Ligand~~\|~~Ligands~~:]]</b></td><td class="sblockDat"~~><scene name='pdbligand=7KF:2-{[(1R,2S)-2-AMINOCYCLOHEXYL]AMINO}-4-[(3-METHYLPHENYL)AMINO]-6,7-DIHYDRO-5H-PYRROLO[3,4-D]PYRIMIDIN-5-ONE'>7KF</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]] 1.77Å</td></tr>
-	~~<tr~~ id~~='related'><td class~~="~~sblockLbl~~">~~<b>~~[[~~Related_structure~~\|~~Related:]]</b></td><td class="sblockDat">[[5tr6\|5tr6~~]]</td></tr>	+	<tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=7KF:2-{[(1R,2S)-2-AMINOCYCLOHEXYL]AMINO}-4-[(3-METHYLPHENYL)AMINO]-6,7-DIHYDRO-5H-PYRROLO[3,4-D]PYRIMIDIN-5-ONE'>7KF</scene></td></tr>
-	<tr id='~~gene~~'><td class="sblockLbl"><b>[[~~Gene~~\|~~Gene~~:]]</b></td><td class="sblockDat"~~>SYK ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&~~id~~=9606 HUMAN])</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=5tt7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5tt7 OCA], [https://pdbe.org/5tt7 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5tt7 RCSB], [https://www.ebi.ac.uk/pdbsum/5tt7 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5tt7 ProSAT]</span></td></tr>
-	~~<tr id='activity'><td class~~="~~sblockLbl~~"><~~b>Activity:</b></td><td class~~=~~"sblockDat"><span class~~=~~'plainlinks'>[http~~:~~//en.wikipedia.org/wiki/Non~~-~~specific_protein~~-~~tyrosine_kinase Non~~-~~specific protein~~-~~tyrosine kinase~~], ~~with EC number~~ [~~http://www.brenda~~-~~enzymes.info/php/result_flat.php4?ecno=2.7.10.2 2.7.10.2~~] </~~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=5tt7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5tt7 OCA], [~~http~~://pdbe.org/5tt7 PDBe], [~~http~~://www.rcsb.org/pdb/explore.do?structureId=5tt7 RCSB], [~~http~~://www.ebi.ac.uk/pdbsum/5tt7 PDBsum], [~~http~~://prosat.h-its.org/prosat/prosatexe?pdbcode=5tt7 ProSAT]</span></td></tr>	+
	</table>		</table>
	== Function ==		== Function ==
-	[~~[http~~://www.uniprot.org/uniprot/KSYK_HUMAN KSYK_HUMAN]] Non-receptor tyrosine kinase which mediates signal transduction downstream of a variety of transmembrane receptors including classical immunoreceptors like the B-cell receptor (BCR). Regulates several biological processes including innate and adaptive immunity, cell adhesion, osteoclast maturation, platelet activation and vascular development. Assembles into signaling complexes with activated receptors at the plasma membrane via interaction between its SH2 domains and the receptor tyrosine-phosphorylated ITAM domains. The association with the receptor can also be indirect and mediated by adapter proteins containing ITAM or partial hemITAM domains. The phosphorylation of the ITAM domains is generally mediated by SRC subfamily kinases upon engagement of the receptor. More rarely signal transduction via SYK could be ITAM-independent. Direct downstream effectors phosphorylated by SYK include VAV1, PLCG1, PI-3-kinase, LCP2 and BLNK. Initially identified as essential in B-cell receptor (BCR) signaling, it is necessary for the maturation of B-cells most probably at the pro-B to pre-B transition. Activated upon BCR engagement, it phosphorylates and activates BLNK an adapter linking the activated BCR to downstream signaling adapters and effectors. It also phosphorylates and activates PLCG1 and the PKC signaling pathway. It also phosphorylates BTK and regulates its activity in B-cell antigen receptor (BCR)-coupled signaling. Beside its function downstream of BCR plays also a role in T-cell receptor signaling. Plays also a crucial role in the innate immune response to fungal, bacterial and viral pathogens. It is for instance activated by the membrane lectin CLEC7A. Upon stimulation by fungal proteins, CLEC7A together with SYK activates immune cells inducing the production of ROS. Also activates the inflammasome and NF-kappa-B-mediated transcription of chemokines and cytokines in presence of pathogens. Regulates neutrophil degranulation and phagocytosis through activation of the MAPK signaling cascade. Also mediates the activation of dendritic cells by cell necrosis stimuli. Also involved in mast cells activation. Also functions downstream of receptors mediating cell adhesion. Relays for instance, integrin-mediated neutrophils and macrophages activation and P-selectin receptor/SELPG-mediated recruitment of leukocytes to inflammatory loci. Plays also a role in non-immune processes. It is for instance involved in vascular development where it may regulate blood and lymphatic vascular separation. It is also required for osteoclast development and function. Functions in the activation of platelets by collagen, mediating PLCG2 phosphorylation and activation. May be coupled to the collagen receptor by the ITAM domain-containing FCER1G. Also activated by the membrane lectin CLEC1B that is required for activation of platelets by PDPN/podoplanin. Involved in platelet adhesion being activated by ITGB3 engaged by fibrinogen.<ref>PMID:8657103</ref> <ref>PMID:9535867</ref> <ref>PMID:12456653</ref> <ref>PMID:12387735</ref> <ref>PMID:15388330</ref> <ref>PMID:19909739</ref>	+	[https://www.uniprot.org/uniprot/KSYK_HUMAN KSYK_HUMAN] Non-receptor tyrosine kinase which mediates signal transduction downstream of a variety of transmembrane receptors including classical immunoreceptors like the B-cell receptor (BCR). Regulates several biological processes including innate and adaptive immunity, cell adhesion, osteoclast maturation, platelet activation and vascular development. Assembles into signaling complexes with activated receptors at the plasma membrane via interaction between its SH2 domains and the receptor tyrosine-phosphorylated ITAM domains. The association with the receptor can also be indirect and mediated by adapter proteins containing ITAM or partial hemITAM domains. The phosphorylation of the ITAM domains is generally mediated by SRC subfamily kinases upon engagement of the receptor. More rarely signal transduction via SYK could be ITAM-independent. Direct downstream effectors phosphorylated by SYK include VAV1, PLCG1, PI-3-kinase, LCP2 and BLNK. Initially identified as essential in B-cell receptor (BCR) signaling, it is necessary for the maturation of B-cells most probably at the pro-B to pre-B transition. Activated upon BCR engagement, it phosphorylates and activates BLNK an adapter linking the activated BCR to downstream signaling adapters and effectors. It also phosphorylates and activates PLCG1 and the PKC signaling pathway. It also phosphorylates BTK and regulates its activity in B-cell antigen receptor (BCR)-coupled signaling. Beside its function downstream of BCR plays also a role in T-cell receptor signaling. Plays also a crucial role in the innate immune response to fungal, bacterial and viral pathogens. It is for instance activated by the membrane lectin CLEC7A. Upon stimulation by fungal proteins, CLEC7A together with SYK activates immune cells inducing the production of ROS. Also activates the inflammasome and NF-kappa-B-mediated transcription of chemokines and cytokines in presence of pathogens. Regulates neutrophil degranulation and phagocytosis through activation of the MAPK signaling cascade. Also mediates the activation of dendritic cells by cell necrosis stimuli. Also involved in mast cells activation. Also functions downstream of receptors mediating cell adhesion. Relays for instance, integrin-mediated neutrophils and macrophages activation and P-selectin receptor/SELPG-mediated recruitment of leukocytes to inflammatory loci. Plays also a role in non-immune processes. It is for instance involved in vascular development where it may regulate blood and lymphatic vascular separation. It is also required for osteoclast development and function. Functions in the activation of platelets by collagen, mediating PLCG2 phosphorylation and activation. May be coupled to the collagen receptor by the ITAM domain-containing FCER1G. Also activated by the membrane lectin CLEC1B that is required for activation of platelets by PDPN/podoplanin. Involved in platelet adhesion being activated by ITGB3 engaged by fibrinogen.<ref>PMID:8657103</ref> <ref>PMID:9535867</ref> <ref>PMID:12456653</ref> <ref>PMID:12387735</ref> <ref>PMID:15388330</ref> <ref>PMID:19909739</ref>
-	~~<div style="background-color:#fffaf0;">~~	+
-	~~== Publication Abstract from PubMed ==~~	+
-	Spleen Tyrosine Kinase (SYK) is a non-receptor cytoplasmic tyrosine kinase that is primarily expressed in hematopoietic cells. SYK is a key mediator for a variety of inflammatory cells, including B cells, mast cells, macrophages and neutrophils and therefore, an attractive approach for treatment of both inflammatory diseases and oncology indications. Using in house co-crystal structure information, and structure-based drug design, we designed and optimized a novel series of heteroaromatic pyrrolidinone SYK inhibitors resulting in the selection of the development candidate TAK-659. TAK-659 is currently undergoing Phase I clinical trials for advanced solid tumor and lymphoma malignancies, a Phase Ib study in advanced solid tumors in combination with nivolumab, and PhIb/II trials for relapsed/refractory AML.	+

-	Discovery of TAK-659 an orally available investigational inhibitor of Spleen Tyrosine Kinase (SYK).,Lam B, Arikawa Y, Cramlett J, Dong Q, de Jong R, Feher V, Grimshaw CE, Farrell PJ, Hoffman ID, Jennings A, Jones B, Matuszkiewicz J, Miura J, Miyake H, Natala SR, Shi L, Takahashi M, Taylor E, Wyrick C, Yano J, Zalevsky J, Nie Z Bioorg Med Chem Lett. 2016 Dec 15;26(24):5947-5950. doi:, 10.1016/j.bmcl.2016.10.087. Epub 2016 Nov 2. PMID:27839918<ref>PMID:27839918</ref>	+	==See Also==
-		+	*[[Tyrosine kinase 3D structures\|Tyrosine kinase 3D structures]]
-	~~From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>~~	+
-	~~</div>~~	+
-	~~<div class~~=~~"pdbe-citations 5tt7" style~~=~~"background-color:#fffaf0;"></div>~~	+
	== References ==		== References ==
	<references/>		<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Human~~]]	+	[[Category: Homo sapiens]]
-	[[Category: ~~Non-specific protein-tyrosine kinase~~]]	+	[[Category: Large Structures]]
-	[[Category: Hoffman~~, I D~~]]	+	[[Category: Hoffman ID]]
-	[[Category: Jennings, A]]	+	[[Category: Jennings A]]
-	[[Category: Lam, B]]	+	[[Category: Lam B]]
-	[[Category: Yano, J]]	+	[[Category: Yano J]]
-	~~[[Category: Inhibitor]]~~	+
-	~~[[Category: Kinase]]~~	+
-	~~[[Category: Leukemia]]~~	+
-	~~[[Category: Lymphoma]]~~	+
-	~~[[Category: Transferase-transferase inhibitor complex~~]]	+

OCA at 10:18, 22 November 2017

OCA — Wed, 22 Nov 2017 10:18:49 GMT

←Older revision		Revision as of 10:18, 22 November 2017
Line 3:		Line 3:
	<StructureSection load='5tt7' size='340' side='right' caption='[[5tt7]], [[Resolution\|resolution]] 1.77Å' scene=''>		<StructureSection load='5tt7' size='340' side='right' caption='[[5tt7]], [[Resolution\|resolution]] 1.77Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[5tt7]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5TT7 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5TT7 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[5tt7]] 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=5TT7 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5TT7 FirstGlance]. <br>
	</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=7KF:2-{[(1R,2S)-2-AMINOCYCLOHEXYL]AMINO}-4-[(3-METHYLPHENYL)AMINO]-6,7-DIHYDRO-5H-PYRROLO[3,4-D]PYRIMIDIN-5-ONE'>7KF</scene></td></tr>		</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand\|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=7KF:2-{[(1R,2S)-2-AMINOCYCLOHEXYL]AMINO}-4-[(3-METHYLPHENYL)AMINO]-6,7-DIHYDRO-5H-PYRROLO[3,4-D]PYRIMIDIN-5-ONE'>7KF</scene></td></tr>
	<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[5tr6\|5tr6]]</td></tr>		<tr id='related'><td class="sblockLbl"><b>[[Related_structure\|Related:]]</b></td><td class="sblockDat">[[5tr6\|5tr6]]</td></tr>
		+	<tr id='gene'><td class="sblockLbl"><b>[[Gene\|Gene:]]</b></td><td class="sblockDat">SYK ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
	<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Non-specific_protein-tyrosine_kinase Non-specific protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.2 2.7.10.2] </span></td></tr>		<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Non-specific_protein-tyrosine_kinase Non-specific protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.2 2.7.10.2] </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=5tt7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5tt7 OCA], [http://pdbe.org/5tt7 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5tt7 RCSB], [http://www.ebi.ac.uk/pdbsum/5tt7 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5tt7 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=5tt7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5tt7 OCA], [http://pdbe.org/5tt7 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5tt7 RCSB], [http://www.ebi.ac.uk/pdbsum/5tt7 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5tt7 ProSAT]</span></td></tr>
Line 24:		Line 25:
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Human]]
	[[Category: Non-specific protein-tyrosine kinase]]		[[Category: Non-specific protein-tyrosine kinase]]
	[[Category: Hoffman, I D]]		[[Category: Hoffman, I D]]

OCA: Protected "5tt7" [edit=sysop:move=sysop]

OCA — Sat, 10 Dec 2016 18:39:25 GMT

Protected "5tt7" [edit=sysop:move=sysop]

←Older revision

Revision as of 18:39, 10 December 2016

OCA: New page: ==Discovery of TAK-659, an Orally Available Investigational Inhibitor of Spleen Tyrosine Kinase (SYK)== == Structural highlights ==
<table><tr><td colspan='2'>[[5tt7]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5TT7 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5TT7 FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=7KF:2-{[(1R,2S)-2-AMINOCYCLOHEXYL]AMINO}-4-[(3-METHYLPHENYL)AMINO]-6,7-DIHYDRO-5H-PYRROLO[3,4-D]PYRIMIDIN-5-ONE'>7KF</scene></td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5tr6|5tr6]]</td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Non-specific_protein-tyrosine_kinase Non-specific protein-tyrosine kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.10.2 2.7.10.2] </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=5tt7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5tt7 OCA], [http://pdbe.org/5tt7 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5tt7 RCSB], [http://www.ebi.ac.uk/pdbsum/5tt7 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5tt7 ProSAT]</span></td></tr>
</table>
== Function ==
[[http://www.uniprot.org/uniprot/KSYK_HUMAN KSYK_HUMAN]] Non-receptor tyrosine kinase which mediates signal transduction downstream of a variety of transmembrane receptors including classical immunoreceptors like the B-cell receptor (BCR). Regulates several biological processes including innate and adaptive immunity, cell adhesion, osteoclast maturation, platelet activation and vascular development. Assembles into signaling complexes with activated receptors at the plasma membrane via interaction between its SH2 domains and the receptor tyrosine-phosphorylated ITAM domains. The association with the receptor can also be indirect and mediated by adapter proteins containing ITAM or partial hemITAM domains. The phosphorylation of the ITAM domains is generally mediated by SRC subfamily kinases upon engagement of the receptor. More rarely signal transduction via SYK could be ITAM-independent. Direct downstream effectors phosphorylated by SYK include VAV1, PLCG1, PI-3-kinase, LCP2 and BLNK. Initially identified as essential in B-cell receptor (BCR) signaling, it is necessary for the maturation of B-cells most probably at the pro-B to pre-B transition. Activated upon BCR engagement, it phosphorylates and activates BLNK an adapter linking the activated BCR to downstream signaling adapters and effectors. It also phosphorylates and activates PLCG1 and the PKC signaling pathway. It also phosphorylates BTK and regulates its activity in B-cell antigen receptor (BCR)-coupled signaling. Beside its function downstream of BCR plays also a role in T-cell receptor signaling. Plays also a crucial role in the innate immune response to fungal, bacterial and viral pathogens. It is for instance activated by the membrane lectin CLEC7A. Upon stimulation by fungal proteins, CLEC7A together with SYK activates immune cells inducing the production of ROS. Also activates the inflammasome and NF-kappa-B-mediated transcription of chemokines and cytokines in presence of pathogens. Regulates neutrophil degranulation and phagocytosis through activation of the MAPK signaling cascade. Also mediates the activation of dendritic cells by cell necrosis stimuli. Also involved in mast cells activation. Also functions downstream of receptors mediating cell adhesion. Relays for instance, integrin-mediated neutrophils and macrophages activation and P-selectin receptor/SELPG-mediated recruitment of leukocytes to inflammatory loci. Plays also a role in non-immune processes. It is for instance involved in vascular development where it may regulate blood and lymphatic vascular separation. It is also required for osteoclast development and function. Functions in the activation of platelets by collagen, mediating PLCG2 phosphorylation and activation. May be coupled to the collagen receptor by the ITAM domain-containing FCER1G. Also activated by the membrane lectin CLEC1B that is required for activation of platelets by PDPN/podoplanin. Involved in platelet adhesion being activated by ITGB3 engaged by fibrinogen.<ref>PMID:8657103</ref> <ref>PMID:9535867</ref> <ref>PMID:12456653</ref> <ref>PMID:12387735</ref> <ref>PMID:15388330</ref> <ref>PMID:19909739</ref>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Spleen Tyrosine Kinase (SYK) is a non-receptor cytoplasmic tyrosine kinase that is primarily expressed in hematopoietic cells. SYK is a key mediator for a variety of inflammatory cells, including B cells, mast cells, macrophages and neutrophils and therefore, an attractive approach for treatment of both inflammatory diseases and oncology indications. Using in house co-crystal structure information, and structure-based drug design, we designed and optimized a novel series of heteroaromatic pyrrolidinone SYK inhibitors resulting in the selection of the development candidate TAK-659. TAK-659 is currently undergoing Phase I clinical trials for advanced solid tumor and lymphoma malignancies, a Phase Ib study in advanced solid tumors in combination with nivolumab, and PhIb/II trials for relapsed/refractory AML.

Discovery of TAK-659 an orally available investigational inhibitor of Spleen Tyrosine Kinase (SYK).,Lam B, Arikawa Y, Cramlett J, Dong Q, de Jong R, Feher V, Grimshaw CE, Farrell PJ, Hoffman ID, Jennings A, Jones B, Matuszkiewicz J, Miura J, Miyake H, Natala SR, Shi L, Takahashi M, Taylor E, Wyrick C, Yano J, Zalevsky J, Nie Z Bioorg Med Chem Lett. 2016 Dec 15;26(24):5947-5950. doi:, 10.1016/j.bmcl.2016.10.087. Epub 2016 Nov 2. PMID:27839918<ref>PMID:27839918</ref>

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 5tt7" style="background-color:#fffaf0;"></div>
== References ==
<references/>
TOC
</StructureSection>
[[Category: Non-specific protein-tyrosine kinase]]
[[Category: Hoffman, I D]]
[[Category: Jennings, A]]
[[Category: Lam, B]]
[[Category: Yano, J]]
[[Category: Inhibitor]]
[[Category: Kinase]]
[[Category: Leukemia]]
[[Category: Lymphoma]]
[[Category: Transferase-transferase inhibitor complex]]