5ovh
From Proteopedia
Ras guanine nucleotide exchange factor SOS1 (Rem-cdc25) in complex with small molecule inhibitor compound 21
Structural highlights
Disease[SOS1_HUMAN] Defects in SOS1 are the cause of gingival fibromatosis 1 (GGF1) [MIM: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.[1] Defects in SOS1 are the cause of Noonan syndrome type 4 (NS4) [MIM: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.[2] [3] [4] [5] [6] [7] [8] [9] Function[SOS1_HUMAN] Promotes the exchange of Ras-bound GDP by GTP. Publication Abstract from PubMedSince the late 1980s, mutations in the RAS genes have been recognized as major oncogenes with a high occurrence rate in human cancers. Such mutations reduce the ability of the small GTPase RAS to hydrolyze GTP, keeping this molecular switch in a constitutively active GTP-bound form that drives, unchecked, oncogenic downstream signaling. One strategy to reduce the levels of active RAS is to target guanine nucleotide exchange factors, which allow RAS to cycle from the inactive GDP-bound state to the active GTP-bound form. Here, we describe the identification of potent and cell-active small-molecule inhibitors which efficiently disrupt the interaction between KRAS and its exchange factor SOS1, a mode of action confirmed by a series of biophysical techniques. The binding sites, mode of action, and selectivity were elucidated using crystal structures of KRAS(G12C)-SOS1, SOS1, and SOS2. By preventing formation of the KRAS-SOS1 complex, these inhibitors block reloading of KRAS with GTP, leading to antiproliferative activity. The final compound 23 (BAY-293) selectively inhibits the KRAS-SOS1 interaction with an IC50 of 21 nM and is a valuable chemical probe for future investigations. Discovery of potent SOS1 inhibitors that block RAS activation via disruption of the RAS-SOS1 interaction.,Hillig RC, Sautier B, Schroeder J, Moosmayer D, Hilpmann A, Stegmann CM, Werbeck ND, Briem H, Boemer U, Weiske J, Badock V, Mastouri J, Petersen K, Siemeister G, Kahmann JD, Wegener D, Bohnke N, Eis K, Graham K, Wortmann L, von Nussbaum F, Bader B Proc Natl Acad Sci U S A. 2019 Feb 12;116(7):2551-2560. doi:, 10.1073/pnas.1812963116. Epub 2019 Jan 25. PMID:30683722[10] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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Categories: Human | Large Structures | Bader, B | Badock, V | Boemer, U | Bohnke, N | Briem, H | Eis, K | Graham, K | Hillig, R C | Hilpmann, A | Kahmann, J | Moosmayer, D | Nussbaum, F von | Petersen, K | Sautier, B | Schroeder, J | Stegmann, C M | Wegener, D | Weiske, J | Wortmann, L | Gef | Guanine exchange factor | Inhibitor | Signaling protein | Sos1
