8xjj
From Proteopedia
(Difference between revisions)
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| - | '''Unreleased structure''' | ||
| - | + | ==Co-crystal structure of SOS-1 and a potent, selective and orally bioavailable SOS1 inhibitor RGT-018== | |
| + | <StructureSection load='8xjj' size='340' side='right'caption='[[8xjj]], [[Resolution|resolution]] 2.10Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[8xjj]] 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=8XJJ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8XJJ 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]] 2.1Å</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=8xjj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8xjj OCA], [https://pdbe.org/8xjj PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8xjj RCSB], [https://www.ebi.ac.uk/pdbsum/8xjj PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8xjj 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 == | ||
| + | KRAS is the most frequently dysregulated oncogene with high prevalence in NSCLC, colorectal cancer, and pancreatic cancer. FDA-approved sotorasib and adagrasib provide breakthrough therapies for cancer patients with KRASG12C mutation. However, there is still high unmet medical need for new agents targeting broader KRAS-driven tumors. An emerging and promising opportunity is to develop a pan KRAS inhibitor by suppressing the upstream protein SOS1. SOS1 is a key activator of KRAS and facilitates the conversion of GDP-bound KRAS state to GTP-bound KRAS state. Binding to its catalytic domain, small molecule SOS1 inhibitor has demonstrated the ability to suppress KRAS activation and cancer cell proliferation. RGT-018, a potent and selective SOS1 inhibitor, was identified with optimal drug-like properties. In vitro, RGT-018 blocked the interaction of KRAS:SOS1 with single digit nM potency and is highly selective against SOS2. RGT-018 inhibited KRAS signaling and the proliferation of a broad spectrum of KRAS-driven cancer cells as a single agent in vitro. Further enhanced anti-proliferation activity was observed when RGT-018 was combined with MEK, KRASG12C, EGFR or CDK4/6 inhibitors. Oral administration of RGT-018 inhibited tumor growth and suppressed KRAS signaling in tumor xenografts in vivo. Combination with MEK or KRASG12C inhibitors led to significant tumor regression. Furthermore, RGT-018 overcame the resistance to the approved KRASG12C inhibitors caused by clinically acquired KRAS mutations either as a single agent or in combination. RGT-018 displayed promising pharmacological properties for combination with targeted agents to treat a broader KRAS-driven patient population. | ||
| - | + | Discovery of RGT-018: a Potent, Selective and Orally Bioavailable SOS1 Inhibitor for KRAS-driven Cancers.,Xiao F, Wang K, Wang X, Li H, Hu Z, Ren X, Huang W, Feng T, Yao L, Lin J, Li C, Zhang Z, Mei L, Zhu X, Zhong W, Xie Z Mol Cancer Ther. 2024 Aug 1. doi: 10.1158/1535-7163.MCT-24-0049. PMID:39087485<ref>PMID:39087485</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| + | <div class="pdbe-citations 8xjj" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Homo sapiens]] | ||
| + | [[Category: Large Structures]] | ||
| + | [[Category: Ren X]] | ||
Current revision
Co-crystal structure of SOS-1 and a potent, selective and orally bioavailable SOS1 inhibitor RGT-018
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