9tk2: Difference between revisions

Line 1:

~~'''Unreleased structure'''~~

~~The~~ entry ~~9tk2~~ is ~~ON HOLD until Paper~~ Publication

==SOS1 IN COMPLEX WITH COMPOUND 3==

== Structural highlights ==

<table><tr><td colspan='2'>[[9tk2]] 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=9TK2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9TK2 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]] 1.924Å</td></tr>

<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1JWK:~{N}6-methyl-~{N}2-[(1~{R})-1-phenylethyl]pyridine-2,6-dicarboxamide'>A1JWK</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=9tk2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9tk2 OCA], [https://pdbe.org/9tk2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9tk2 RCSB], [https://www.ebi.ac.uk/pdbsum/9tk2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9tk2 ProSAT]</span></td></tr>

</table>

== Disease ==

[https://www.uniprot.org/uniprot/SOS1_HUMAN SOS1_HUMAN] Defects in SOS1 are the cause of gingival fibromatosis 1 (GGF1) [MIM:[https://omim.org/entry/135300 135300]; also known as GINGF1. Gingival fibromatosis is a rare overgrowth condition characterized by a benign, slowly progressive, nonhemorrhagic, fibrous enlargement of maxillary and mandibular keratinized gingiva. GGF1 is usually transmitted as an autosomal dominant trait, although sporadic cases are common.<ref>PMID:11868160</ref> Defects in SOS1 are the cause of Noonan syndrome type 4 (NS4) [MIM:[https://omim.org/entry/610733 610733]. NS4 is an autosomal dominant disorder characterized by dysmorphic facial features, short stature, hypertelorism, cardiac anomalies, deafness, motor delay, and a bleeding diathesis. It is a genetically heterogeneous and relatively common syndrome, with an estimated incidence of 1 in 1000-2500 live births. Rarely, NS4 is associated with juvenile myelomonocytic leukemia (JMML). SOS1 mutations engender a high prevalence of pulmonary valve disease; atrial septal defects are less common.<ref>PMID:17143285</ref> <ref>PMID:17143282</ref> <ref>PMID:19020799</ref> <ref>PMID:19438935</ref> <ref>PMID:20683980</ref> <ref>PMID:20673819</ref> <ref>PMID:19953625</ref> <ref>PMID:21387466</ref>

== Function ==

[https://www.uniprot.org/uniprot/SOS1_HUMAN SOS1_HUMAN] Promotes the exchange of Ras-bound GDP by GTP.

== Publication Abstract from PubMed ==

Son of Sevenless Homologue 1 (SOS1) is a promising oncology target with inhibitors in phase 1/2 clinical studies. A focused HTS triage led to a singular SOS1 series having a pyridyl core. The conformational preference of the diamide pyridyl core was critical to binding potency, leading to pyrazine and pyridyl being the preferred motifs. Application of structure-based design to build into a buried lipophilic pocket led to a significant 50-fold potency enhancement. Strategic fluorination of aryl rings and substituents generated compounds with favorable dipoles, low P-gp and BCRP efflux, and high rat Kp(u,u). Multiple analogues were progressed into in vivo PK/PD studies where they were combined with a KRAS(G12C) inhibitor. Combination treated tumors in mice showed deeper, more sustained reductions in DUSP6 mRNA and phosphorylated ERK compared to KRAS(G12C) inhibitor alone. Thus, these novel CNS penetrant SOS1 inhibitors have potential to enhance antitumor responses when combined with RAS or MAPK inhibitors.

~~Authors~~:

Discovery of CNS Penetrant SOS1 Inhibitors for the Treatment of KRAS-Dependent Cancers.,Bagal SK, Diene CRN, Stefanovic-Barrett S, Breed J, Kauffman GW, Bodnarchuk MS, Collie GW, Staniszewska AD, Srivastava A, Irving E, Cassar DJ, Gray S, Hughes C, Kettle JG, Nash S, Northall S, Peter A, Schade M, Stubbs CJ, Smith A, Young L J Med Chem. 2026 Jun 16. doi: 10.1021/acs.jmedchem.5c03800. PMID:42301273<ref>PMID:42301273</ref>

~~Description~~:

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

[[Category: ~~Unreleased~~ Structures]]

</div>

== References ==

__TOC__

</StructureSection>

[[Category: Homo sapiens]]

[[Category: Large Structures]]

[[Category: Breed J]]

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@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 9tk2 is ON HOLD  until Paper Publication
+==SOS1 IN COMPLEX WITH COMPOUND 3==
+<StructureSection load='9tk2' size='340' side='right'caption='[[9tk2]], [[Resolution|resolution]] 1.92&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[9tk2]] 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=9TK2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9TK2 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]] 1.924&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1JWK:~{N}6-methyl-~{N}2-[(1~{R})-1-phenylethyl]pyridine-2,6-dicarboxamide'>A1JWK</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=9tk2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9tk2 OCA], [https://pdbe.org/9tk2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9tk2 RCSB], [https://www.ebi.ac.uk/pdbsum/9tk2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9tk2 ProSAT]</span></td></tr>
+</table>
+== Disease ==
+[https://www.uniprot.org/uniprot/SOS1_HUMAN SOS1_HUMAN] Defects in SOS1 are the cause of gingival fibromatosis 1 (GGF1) [MIM:[https://omim.org/entry/135300 135300]; also known as GINGF1. Gingival fibromatosis is a rare overgrowth condition characterized by a benign, slowly progressive, nonhemorrhagic, fibrous enlargement of maxillary and mandibular keratinized gingiva. GGF1 is usually transmitted as an autosomal dominant trait, although sporadic cases are common.<ref>PMID:11868160</ref>   Defects in SOS1 are the cause of Noonan syndrome type 4 (NS4) [MIM:[https://omim.org/entry/610733 610733]. NS4 is an autosomal dominant disorder characterized by dysmorphic facial features, short stature, hypertelorism, cardiac anomalies, deafness, motor delay, and a bleeding diathesis. It is a genetically heterogeneous and relatively common syndrome, with an estimated incidence of 1 in 1000-2500 live births. Rarely, NS4 is associated with juvenile myelomonocytic leukemia (JMML). SOS1 mutations engender a high prevalence of pulmonary valve disease; atrial septal defects are less common.<ref>PMID:17143285</ref> <ref>PMID:17143282</ref> <ref>PMID:19020799</ref> <ref>PMID:19438935</ref> <ref>PMID:20683980</ref> <ref>PMID:20673819</ref> <ref>PMID:19953625</ref> <ref>PMID:21387466</ref>
+== Function ==
+[https://www.uniprot.org/uniprot/SOS1_HUMAN SOS1_HUMAN] Promotes the exchange of Ras-bound GDP by GTP.
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Son of Sevenless Homologue 1 (SOS1) is a promising oncology target with inhibitors in phase 1/2 clinical studies. A focused HTS triage led to a singular SOS1 series having a pyridyl core. The conformational preference of the diamide pyridyl core was critical to binding potency, leading to pyrazine and pyridyl being the preferred motifs. Application of structure-based design to build into a buried lipophilic pocket led to a significant 50-fold potency enhancement. Strategic fluorination of aryl rings and substituents generated compounds with favorable dipoles, low P-gp and BCRP efflux, and high rat Kp(u,u). Multiple analogues were progressed into in vivo PK/PD studies where they were combined with a KRAS(G12C) inhibitor. Combination treated tumors in mice showed deeper, more sustained reductions in DUSP6 mRNA and phosphorylated ERK compared to KRAS(G12C) inhibitor alone. Thus, these novel CNS penetrant SOS1 inhibitors have potential to enhance antitumor responses when combined with RAS or MAPK inhibitors.
-Authors:
+Discovery of CNS Penetrant SOS1 Inhibitors for the Treatment of KRAS-Dependent Cancers.,Bagal SK, Diene CRN, Stefanovic-Barrett S, Breed J, Kauffman GW, Bodnarchuk MS, Collie GW, Staniszewska AD, Srivastava A, Irving E, Cassar DJ, Gray S, Hughes C, Kettle JG, Nash S, Northall S, Peter A, Schade M, Stubbs CJ, Smith A, Young L J Med Chem. 2026 Jun 16. doi: 10.1021/acs.jmedchem.5c03800. PMID:42301273<ref>PMID:42301273</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 9tk2" style="background-color:#fffaf0;"></div>
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Homo sapiens]]
+[[Category: Large Structures]]
+[[Category: Breed J]]