A Sos proteomimetic as a pan-Ras inhibitor
Aberrant Ras signaling is linked to a wide spectrum of hyperproliferative diseases, and components of the signaling pathway, including Ras, have been the subject of intense and ongoing drug discovery efforts. The cellular activity of Ras is modulated by its association with the guanine nucleotide ex...
Saved in:
| Published in | Proceedings of the National Academy of Sciences - PNAS Vol. 118; no. 18; pp. 1 - 11 |
|---|---|
| Main Authors | , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
National Academy of Sciences
04.05.2021
|
| Subjects | |
| Online Access | Get full text |
Cover
Loading…
| Abstract | Aberrant Ras signaling is linked to a wide spectrum of hyperproliferative diseases, and components of the signaling pathway, including Ras, have been the subject of intense and ongoing drug discovery efforts. The cellular activity of Ras is modulated by its association with the guanine nucleotide exchange factor Son of sevenless (Sos), and the high-resolution crystal structure of the Ras–Sos complex provides a basis for the rational design of orthosteric Ras ligands. We constructed a synthetic Sos protein mimic that engages the wild-type and oncogenic forms of nucleotide-bound Ras and modulates downstream kinase signaling. The Sos mimic was designed to capture the conformation of the Sos helix–loop–helix motif that makes critical contacts with Ras in its switch region. Chemoproteomic studies illustrate that the proteomimetic engages Ras and other cellular GTPases. The synthetic proteomimetic resists proteolytic degradation and enters cells through macropinocytosis. As such, it is selectively toxic to cancer cells with upregulated macropinocytosis, including those that feature oncogenic Ras mutations. |
|---|---|
| AbstractList | Oncogenic Ras isoforms are the subject of intense study due to the difficulty in targeting these biomedically important yet “undruggable” proteins. Recent success in covalent targeting of a Ras mutant illustrates avenues for ligand design; however, many mutant Ras forms do not feature appropriately-placed nucleophiles, suggesting that strategies for noncovalent engagement of Ras are required. We report the design of a conformationally-defined proteomimetic that reproduces a key binding surface of Sos, a well-characterized effector of Ras. The proteomimetic binds wild-type and various mutant forms of Ras and modulates downstream signaling. Significantly, the compound shows enhanced internalization and selective toxicity toward cancer cells that up-regulate macropinocytosis. We anticipate these studies will foster new therapeutic modalities to engage mutant Ras.
Aberrant Ras signaling is linked to a wide spectrum of hyperproliferative diseases, and components of the signaling pathway, including Ras, have been the subject of intense and ongoing drug discovery efforts. The cellular activity of Ras is modulated by its association with the guanine nucleotide exchange factor Son of sevenless (Sos), and the high-resolution crystal structure of the Ras–Sos complex provides a basis for the rational design of orthosteric Ras ligands. We constructed a synthetic Sos protein mimic that engages the wild-type and oncogenic forms of nucleotide-bound Ras and modulates downstream kinase signaling. The Sos mimic was designed to capture the conformation of the Sos helix–loop–helix motif that makes critical contacts with Ras in its switch region. Chemoproteomic studies illustrate that the proteomimetic engages Ras and other cellular GTPases. The synthetic proteomimetic resists proteolytic degradation and enters cells through macropinocytosis. As such, it is selectively toxic to cancer cells with up-regulated macropinocytosis, including those that feature oncogenic Ras mutations. Aberrant Ras signaling is linked to a wide spectrum of hyperproliferative diseases, and components of the signaling pathway, including Ras, have been the subject of intense and ongoing drug discovery efforts. The cellular activity of Ras is modulated by its association with the guanine nucleotide exchange factor Son of sevenless (Sos), and the high-resolution crystal structure of the Ras-Sos complex provides a basis for the rational design of orthosteric Ras ligands. We constructed a synthetic Sos protein mimic that engages the wild-type and oncogenic forms of nucleotide-bound Ras and modulates downstream kinase signaling. The Sos mimic was designed to capture the conformation of the Sos helix-loop-helix motif that makes critical contacts with Ras in its switch region. Chemoproteomic studies illustrate that the proteomimetic engages Ras and other cellular GTPases. The synthetic proteomimetic resists proteolytic degradation and enters cells through macropinocytosis. As such, it is selectively toxic to cancer cells with up-regulated macropinocytosis, including those that feature oncogenic Ras mutations. Aberrant Ras signaling is linked to a wide spectrum of hyperproliferative diseases, and components of the signaling pathway, including Ras, have been the subject of intense and ongoing drug discovery efforts. The cellular activity of Ras is modulated by its association with the guanine nucleotide exchange factor Son of sevenless (Sos), and the high-resolution crystal structure of the Ras-Sos complex provides a basis for the rational design of orthosteric Ras ligands. We constructed a synthetic Sos protein mimic that engages the wild-type and oncogenic forms of nucleotide-bound Ras and modulates downstream kinase signaling. The Sos mimic was designed to capture the conformation of the Sos helix-loop-helix motif that makes critical contacts with Ras in its switch region. Chemoproteomic studies illustrate that the proteomimetic engages Ras and other cellular GTPases. The synthetic proteomimetic resists proteolytic degradation and enters cells through macropinocytosis. As such, it is selectively toxic to cancer cells with up-regulated macropinocytosis, including those that feature oncogenic Ras mutations.Aberrant Ras signaling is linked to a wide spectrum of hyperproliferative diseases, and components of the signaling pathway, including Ras, have been the subject of intense and ongoing drug discovery efforts. The cellular activity of Ras is modulated by its association with the guanine nucleotide exchange factor Son of sevenless (Sos), and the high-resolution crystal structure of the Ras-Sos complex provides a basis for the rational design of orthosteric Ras ligands. We constructed a synthetic Sos protein mimic that engages the wild-type and oncogenic forms of nucleotide-bound Ras and modulates downstream kinase signaling. The Sos mimic was designed to capture the conformation of the Sos helix-loop-helix motif that makes critical contacts with Ras in its switch region. Chemoproteomic studies illustrate that the proteomimetic engages Ras and other cellular GTPases. The synthetic proteomimetic resists proteolytic degradation and enters cells through macropinocytosis. As such, it is selectively toxic to cancer cells with up-regulated macropinocytosis, including those that feature oncogenic Ras mutations. Aberrant Ras signaling is linked to a wide spectrum of hyperproliferative diseases, and components of the signaling pathway, including Ras, have been the subject of intense and ongoing drug discovery efforts. The cellular activity of Ras is modulated by its association with the guanine nucleotide exchange factor Son of sevenless (Sos), and the high-resolution crystal structure of the Ras–Sos complex provides a basis for the rational design of orthosteric Ras ligands. We constructed a synthetic Sos protein mimic that engages the wild-type and oncogenic forms of nucleotide-bound Ras and modulates downstream kinase signaling. The Sos mimic was designed to capture the conformation of the Sos helix–loop–helix motif that makes critical contacts with Ras in its switch region. Chemoproteomic studies illustrate that the proteomimetic engages Ras and other cellular GTPases. The synthetic proteomimetic resists proteolytic degradation and enters cells through macropinocytosis. As such, it is selectively toxic to cancer cells with upregulated macropinocytosis, including those that feature oncogenic Ras mutations. |
| Author | Hong, Seong Ho Yoo, Daniel Y. Arora, Paramjit S. Parker, Christopher G. Conway, Louis Richards-Corke, Khyle C. |
| Author_xml | – sequence: 1 givenname: Seong Ho surname: Hong fullname: Hong, Seong Ho – sequence: 2 givenname: Daniel Y. surname: Yoo fullname: Yoo, Daniel Y. – sequence: 3 givenname: Louis surname: Conway fullname: Conway, Louis – sequence: 4 givenname: Khyle C. surname: Richards-Corke fullname: Richards-Corke, Khyle C. – sequence: 5 givenname: Christopher G. surname: Parker fullname: Parker, Christopher G. – sequence: 6 givenname: Paramjit S. surname: Arora fullname: Arora, Paramjit S. |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/33926964$$D View this record in MEDLINE/PubMed |
| BookMark | eNp9kUtr3DAUhUVIyUwe66waDN2UgpOrh_XYFIahbQqBQNKuheyRGw225EieQv99ZWYyeSyyktD9zrn36hyjQx-8RegcwyUGQa8Gb9IlwYCBCIzlAZpjULjkTMEhmkN-LSUjbIaOU1oDgKokHKEZpYpwxdkcfVkU9yEVQwyjDb3r7eiawqTCFIPx5V2-Of_gajeGeIo-tKZL9mx3nqDf37_9Wl6XN7c_fi4XN2XDGB3LFmpbY14r09YtlUAqLIVoFcOi5VwJbowyilpreS1lW1UrWwuilF2tjBBK0BP0des7bOrerhrrx2g6PUTXm_hPB-P064p3D_pP-KslBk5UlQ0-7wxieNzYNOrepcZ2nfE2bJImFQEpQXCW0U9v0HXYRJ_XmyiKuQQ5URcvJ9qP8vSNGbjaAk0MKUXb7hEMegpKT0Hp56CyonqjaNxoRhemlVz3ju7jVrdOOZJ9GyKAAc31_5UYn-4 |
| CitedBy_id | crossref_primary_10_1038_s41401_022_00897_4 crossref_primary_10_1021_acs_jmedchem_1c01130 crossref_primary_10_1002_cbic_202200561 crossref_primary_10_1002_cpz1_315 crossref_primary_10_1021_jacs_1c13717 crossref_primary_10_1038_s42004_022_00691_7 crossref_primary_10_1038_s41392_024_01823_2 crossref_primary_10_1021_acs_chemrev_4c00423 crossref_primary_10_1038_s41392_023_01441_4 crossref_primary_10_1016_j_bioorg_2023_106500 crossref_primary_10_1002_adma_202208309 crossref_primary_10_1002_cbic_202100111 crossref_primary_10_1021_acsinfecdis_1c00651 crossref_primary_10_1039_D1OB01353J crossref_primary_10_1021_acs_jmedchem_2c01729 crossref_primary_10_1016_j_ejmech_2024_116878 crossref_primary_10_1016_j_ejmech_2025_117568 crossref_primary_10_1038_s41589_022_01060_0 crossref_primary_10_1016_j_tips_2021_11_008 crossref_primary_10_3390_ijms22126613 |
| Cites_doi | 10.1002/bip.360310511 10.1021/bi970296u 10.1021/ja208855x 10.1038/srep32301 10.1021/jacs.7b05960 10.1016/j.chembiol.2017.10.001 10.1177/1947601911408081 10.1038/nrc2960 10.1038/s41557-020-0420-9 10.1038/nchembio.2231 10.1038/nrc969 10.1021/jacs.8b10082 10.1038/nrm2901 10.1038/nchembio.612 10.1002/anie.201201358 10.1038/nrd.2016.139 10.1016/j.trecan.2018.07.002 10.1073/pnas.2009206117 10.1016/j.cell.2016.12.029 10.1038/nrd2221 10.1021/jacs.5b05527 10.1517/17425247.2015.1046431 10.1073/pnas.1312473110 10.1073/pnas.1116510109 10.1126/stke.2192004pl2 10.1021/sb300028q 10.1038/srep21949 10.1016/S0092-8674(03)00149-1 10.1016/j.cell.2020.01.025 10.1093/nar/gkq369 10.1016/j.ccr.2014.02.017 10.1002/jcc.20084 10.1038/s41467-020-19224-8 10.1038/s41573-020-0068-6 10.1126/stke.2502004re13 10.1016/j.cell.2017.02.006 10.1002/9780470559277.ch090102 10.1038/s41467-020-15576-3 10.1021/acs.jmedchem.9b01180 10.1038/s41557-019-0351-5 10.1073/pnas.1815294115 10.1038/s41586-019-1694-1 10.1073/pnas.1303002110 10.1073/pnas.0709068105 10.1038/nature12138 10.1038/nature12796 10.1007/978-1-4757-2508-7_7 10.1038/28548 10.1186/s12953-017-0123-3 10.1126/science.271.5252.1136 10.1021/acscentsci.0c00514 10.1021/jacs.5b05525 10.1016/j.cell.2004.10.005 10.1002/anie.201412070 10.1126/science.1604319 10.1038/s41598-020-78712-5 10.1021/ac502040v 10.1038/nrd4281 10.1021/acschembio.0c00204 10.1021/acs.jmedchem.0c01312 10.1021/jacs.0c02109 |
| ContentType | Journal Article |
| Copyright | Copyright National Academy of Sciences May 4, 2021 2021 |
| Copyright_xml | – notice: Copyright National Academy of Sciences May 4, 2021 – notice: 2021 |
| DBID | AAYXX CITATION NPM 7QG 7QL 7QP 7QR 7SN 7SS 7T5 7TK 7TM 7TO 7U9 8FD C1K FR3 H94 M7N P64 RC3 7X8 5PM |
| DOI | 10.1073/pnas.2101027118 |
| DatabaseName | CrossRef PubMed Animal Behavior Abstracts Bacteriology Abstracts (Microbiology B) Calcium & Calcified Tissue Abstracts Chemoreception Abstracts Ecology Abstracts Entomology Abstracts (Full archive) Immunology Abstracts Neurosciences Abstracts Nucleic Acids Abstracts Oncogenes and Growth Factors Abstracts Virology and AIDS Abstracts Technology Research Database Environmental Sciences and Pollution Management Engineering Research Database AIDS and Cancer Research Abstracts Algology Mycology and Protozoology Abstracts (Microbiology C) Biotechnology and BioEngineering Abstracts Genetics Abstracts MEDLINE - Academic PubMed Central (Full Participant titles) |
| DatabaseTitle | CrossRef PubMed Virology and AIDS Abstracts Oncogenes and Growth Factors Abstracts Technology Research Database Nucleic Acids Abstracts Ecology Abstracts Neurosciences Abstracts Biotechnology and BioEngineering Abstracts Environmental Sciences and Pollution Management Entomology Abstracts Genetics Abstracts Animal Behavior Abstracts Bacteriology Abstracts (Microbiology B) Algology Mycology and Protozoology Abstracts (Microbiology C) AIDS and Cancer Research Abstracts Chemoreception Abstracts Immunology Abstracts Engineering Research Database Calcium & Calcified Tissue Abstracts MEDLINE - Academic |
| DatabaseTitleList | CrossRef PubMed Virology and AIDS Abstracts MEDLINE - Academic |
| Database_xml | – sequence: 1 dbid: NPM name: PubMed url: https://proxy.k.utb.cz/login?url=http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed sourceTypes: Index Database |
| DeliveryMethod | fulltext_linktorsrc |
| Discipline | Sciences (General) |
| EISSN | 1091-6490 |
| EndPage | 11 |
| ExternalDocumentID | PMC8106295 33926964 10_1073_pnas_2101027118 27040318 |
| Genre | Journal Article |
| GrantInformation_xml | – fundername: HHS | NIH | National Institute of General Medical Sciences (NIGMS) grantid: R35GM130333 |
| GroupedDBID | --- -DZ -~X .55 0R~ 123 29P 2AX 2FS 2WC 4.4 53G 5RE 5VS 85S AACGO AAFWJ AANCE ABBHK ABOCM ABPLY ABPPZ ABTLG ABXSQ ABZEH ACGOD ACIWK ACNCT ACPRK AENEX AEUPB AEXZC AFFNX AFOSN AFRAH ALMA_UNASSIGNED_HOLDINGS BKOMP CS3 D0L DCCCD DIK DU5 E3Z EBS F5P FRP GX1 H13 HH5 HYE IPSME JAAYA JBMMH JENOY JHFFW JKQEH JLS JLXEF JPM JSG JST KQ8 L7B LU7 N9A N~3 O9- OK1 PNE PQQKQ R.V RHI RNA RNS RPM RXW SA0 SJN TAE TN5 UKR W8F WH7 WOQ WOW X7M XSW Y6R YBH YKV YSK ZCA ~02 ~KM AAYXX CITATION NPM RHF VQA YIF YIN 7QG 7QL 7QP 7QR 7SN 7SS 7T5 7TK 7TM 7TO 7U9 8FD C1K FR3 H94 M7N P64 RC3 7X8 5PM |
| ID | FETCH-LOGICAL-c443t-f0beb16b9afbf380251877f9417f66976aa9a93eee6b88f55deb7299edda77973 |
| ISSN | 0027-8424 1091-6490 |
| IngestDate | Thu Aug 21 18:34:30 EDT 2025 Thu Jul 10 23:27:04 EDT 2025 Mon Jun 30 08:27:54 EDT 2025 Wed Feb 19 02:27:27 EST 2025 Thu Apr 24 22:54:40 EDT 2025 Tue Jul 01 01:02:55 EDT 2025 Thu May 29 08:53:14 EDT 2025 |
| IsDoiOpenAccess | false |
| IsOpenAccess | true |
| IsPeerReviewed | true |
| IsScholarly | true |
| Issue | 18 |
| Keywords | peptide proteomimetic Ras Sos |
| Language | English |
| License | Published under the PNAS license. |
| LinkModel | OpenURL |
| MergedId | FETCHMERGED-LOGICAL-c443t-f0beb16b9afbf380251877f9417f66976aa9a93eee6b88f55deb7299edda77973 |
| Notes | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 Edited by Daniel-Adriano Silva, Neoleukin Therapeutics, Seattle, WA, and accepted by Editorial Board Member Stephen J. Benkovic March 19, 2021 (received for review January 18, 2021) 1S.H.H. and D.Y.Y. contributed equally to this work. Author contributions: S.H.H., D.Y.Y., and P.S.A. designed research; S.H.H., D.Y.Y., L.C., K.C.R.-C., and C.G.P. performed research; S.H.H., D.Y.Y., L.C., C.G.P., and P.S.A. analyzed data; and S.H.H., D.Y.Y., and P.S.A. wrote the paper. |
| ORCID | 0000-0001-8509-9289 0000-0002-8928-2686 0000-0002-8634-452X 0000-0002-5433-0115 0000-0001-5315-401X |
| OpenAccessLink | https://www.pnas.org/content/pnas/118/18/e2101027118.full.pdf |
| PMID | 33926964 |
| PQID | 2523168084 |
| PQPubID | 42026 |
| PageCount | 11 |
| ParticipantIDs | pubmedcentral_primary_oai_pubmedcentral_nih_gov_8106295 proquest_miscellaneous_2520880764 proquest_journals_2523168084 pubmed_primary_33926964 crossref_primary_10_1073_pnas_2101027118 crossref_citationtrail_10_1073_pnas_2101027118 jstor_primary_27040318 |
| ProviderPackageCode | CITATION AAYXX |
| PublicationCentury | 2000 |
| PublicationDate | 2021-05-04 |
| PublicationDateYYYYMMDD | 2021-05-04 |
| PublicationDate_xml | – month: 05 year: 2021 text: 2021-05-04 day: 04 |
| PublicationDecade | 2020 |
| PublicationPlace | United States |
| PublicationPlace_xml | – name: United States – name: Washington |
| PublicationTitle | Proceedings of the National Academy of Sciences - PNAS |
| PublicationTitleAlternate | Proc Natl Acad Sci U S A |
| PublicationYear | 2021 |
| Publisher | National Academy of Sciences |
| Publisher_xml | – name: National Academy of Sciences |
| References | e_1_3_4_3_2 e_1_3_4_1_2 e_1_3_4_61_2 e_1_3_4_9_2 e_1_3_4_7_2 e_1_3_4_5_2 e_1_3_4_23_2 e_1_3_4_44_2 e_1_3_4_21_2 e_1_3_4_42_2 Taylor S. J. (e_1_3_4_40_2) 2001 e_1_3_4_27_2 e_1_3_4_48_2 e_1_3_4_25_2 e_1_3_4_46_2 e_1_3_4_29_2 e_1_3_4_30_2 e_1_3_4_51_2 e_1_3_4_11_2 e_1_3_4_34_2 e_1_3_4_57_2 e_1_3_4_55_2 e_1_3_4_32_2 e_1_3_4_59_2 e_1_3_4_53_2 e_1_3_4_15_2 e_1_3_4_38_2 e_1_3_4_13_2 e_1_3_4_36_2 e_1_3_4_19_2 e_1_3_4_17_2 e_1_3_4_2_2 e_1_3_4_60_2 e_1_3_4_62_2 e_1_3_4_8_2 e_1_3_4_41_2 e_1_3_4_6_2 e_1_3_4_4_2 e_1_3_4_22_2 e_1_3_4_45_2 e_1_3_4_20_2 e_1_3_4_43_2 e_1_3_4_26_2 e_1_3_4_49_2 e_1_3_4_24_2 e_1_3_4_47_2 e_1_3_4_28_2 e_1_3_4_52_2 e_1_3_4_50_2 e_1_3_4_12_2 e_1_3_4_33_2 e_1_3_4_58_2 e_1_3_4_54_2 e_1_3_4_10_2 e_1_3_4_31_2 e_1_3_4_16_2 e_1_3_4_37_2 e_1_3_4_14_2 e_1_3_4_35_2 e_1_3_4_56_2 e_1_3_4_18_2 e_1_3_4_39_2 |
| References_xml | – ident: e_1_3_4_33_2 doi: 10.1002/bip.360310511 – ident: e_1_3_4_61_2 doi: 10.1021/bi970296u – ident: e_1_3_4_25_2 doi: 10.1021/ja208855x – ident: e_1_3_4_36_2 doi: 10.1038/srep32301 – ident: e_1_3_4_23_2 doi: 10.1021/jacs.7b05960 – ident: e_1_3_4_58_2 doi: 10.1016/j.chembiol.2017.10.001 – ident: e_1_3_4_39_2 doi: 10.1177/1947601911408081 – ident: e_1_3_4_43_2 doi: 10.1038/nrc2960 – ident: e_1_3_4_16_2 doi: 10.1038/s41557-020-0420-9 – ident: e_1_3_4_50_2 doi: 10.1038/nchembio.2231 – ident: e_1_3_4_55_2 doi: 10.1038/nrc969 – ident: e_1_3_4_20_2 doi: 10.1021/jacs.8b10082 – ident: e_1_3_4_11_2 doi: 10.1038/nrm2901 – ident: e_1_3_4_10_2 doi: 10.1038/nchembio.612 – ident: e_1_3_4_53_2 doi: 10.1002/anie.201201358 – ident: e_1_3_4_54_2 doi: 10.1038/nrd.2016.139 – ident: e_1_3_4_41_2 doi: 10.1016/j.trecan.2018.07.002 – ident: e_1_3_4_62_2 doi: 10.1073/pnas.2009206117 – ident: e_1_3_4_45_2 doi: 10.1016/j.cell.2016.12.029 – ident: e_1_3_4_1_2 doi: 10.1038/nrd2221 – ident: e_1_3_4_19_2 doi: 10.1021/jacs.5b05527 – ident: e_1_3_4_37_2 doi: 10.1517/17425247.2015.1046431 – ident: e_1_3_4_13_2 doi: 10.1073/pnas.1312473110 – ident: e_1_3_4_52_2 doi: 10.1073/pnas.1116510109 – ident: e_1_3_4_24_2 doi: 10.1126/stke.2192004pl2 – ident: e_1_3_4_27_2 doi: 10.1021/sb300028q – ident: e_1_3_4_38_2 doi: 10.1038/srep21949 – ident: e_1_3_4_60_2 doi: 10.1016/S0092-8674(03)00149-1 – ident: e_1_3_4_44_2 doi: 10.1016/j.cell.2020.01.025 – ident: e_1_3_4_22_2 doi: 10.1093/nar/gkq369 – ident: e_1_3_4_56_2 doi: 10.1016/j.ccr.2014.02.017 – ident: e_1_3_4_29_2 doi: 10.1002/jcc.20084 – ident: e_1_3_4_17_2 doi: 10.1038/s41467-020-19224-8 – ident: e_1_3_4_3_2 doi: 10.1038/s41573-020-0068-6 – ident: e_1_3_4_49_2 doi: 10.1126/stke.2502004re13 – ident: e_1_3_4_51_2 doi: 10.1016/j.cell.2017.02.006 – ident: e_1_3_4_31_2 doi: 10.1002/9780470559277.ch090102 – ident: e_1_3_4_18_2 doi: 10.1038/s41467-020-15576-3 – ident: e_1_3_4_57_2 doi: 10.1021/acs.jmedchem.9b01180 – ident: e_1_3_4_46_2 doi: 10.1038/s41557-019-0351-5 – ident: e_1_3_4_14_2 doi: 10.1073/pnas.1815294115 – ident: e_1_3_4_5_2 doi: 10.1038/s41586-019-1694-1 – start-page: 333 volume-title: Methods in Enzymology year: 2001 ident: e_1_3_4_40_2 – ident: e_1_3_4_12_2 doi: 10.1073/pnas.1303002110 – ident: e_1_3_4_26_2 doi: 10.1073/pnas.0709068105 – ident: e_1_3_4_35_2 doi: 10.1038/nature12138 – ident: e_1_3_4_6_2 doi: 10.1038/nature12796 – ident: e_1_3_4_32_2 doi: 10.1007/978-1-4757-2508-7_7 – ident: e_1_3_4_2_2 doi: 10.1038/28548 – ident: e_1_3_4_59_2 doi: 10.1186/s12953-017-0123-3 – ident: e_1_3_4_28_2 doi: 10.1126/science.271.5252.1136 – ident: e_1_3_4_7_2 doi: 10.1021/acscentsci.0c00514 – ident: e_1_3_4_21_2 doi: 10.1021/jacs.5b05525 – ident: e_1_3_4_30_2 doi: 10.1016/j.cell.2004.10.005 – ident: e_1_3_4_15_2 doi: 10.1002/anie.201412070 – ident: e_1_3_4_48_2 doi: 10.1126/science.1604319 – ident: e_1_3_4_8_2 doi: 10.1038/s41598-020-78712-5 – ident: e_1_3_4_47_2 doi: 10.1021/ac502040v – ident: e_1_3_4_42_2 doi: 10.1038/nrd4281 – ident: e_1_3_4_9_2 doi: 10.1021/acschembio.0c00204 – ident: e_1_3_4_4_2 doi: 10.1021/acs.jmedchem.0c01312 – ident: e_1_3_4_34_2 doi: 10.1021/jacs.0c02109 |
| SSID | ssj0009580 |
| Score | 2.4773583 |
| Snippet | Aberrant Ras signaling is linked to a wide spectrum of hyperproliferative diseases, and components of the signaling pathway, including Ras, have been the... Oncogenic Ras isoforms are the subject of intense study due to the difficulty in targeting these biomedically important yet “undruggable” proteins. Recent... |
| SourceID | pubmedcentral proquest pubmed crossref jstor |
| SourceType | Open Access Repository Aggregation Database Index Database Enrichment Source Publisher |
| StartPage | 1 |
| SubjectTerms | Biological Sciences Crystal structure Guanine Guanine nucleotide exchange factor Kinases Mutation Nucleotides Physical Sciences Proteolysis Ras protein Signal transduction Signaling |
| Title | A Sos proteomimetic as a pan-Ras inhibitor |
| URI | https://www.jstor.org/stable/27040318 https://www.ncbi.nlm.nih.gov/pubmed/33926964 https://www.proquest.com/docview/2523168084 https://www.proquest.com/docview/2520880764 https://pubmed.ncbi.nlm.nih.gov/PMC8106295 |
| Volume | 118 |
| hasFullText | 1 |
| inHoldings | 1 |
| isFullTextHit | |
| isPrint | |
| link | http://utb.summon.serialssolutions.com/2.0.0/link/0/eLvHCXMwnV3db9MwELdgvPCCGDAoDBQkHgaRSxI7dvJYVZsqmMrEWqlvkZPYaqQtQaQVgr-ec2I76yjS4CWK_NXIdz7fXe9-h9C7koCMg5OEi4BEmIqCYdCTQ5ywJKZ5XOraODraYs5mS_ppFa9svXuTXbLJx8WvvXkl_0NVaAO66izZf6CsWxQa4B3oC0-gMDzvROOJf9m0fge10FxX17IDX2194cMRx1-FDrVaV3nVAwo7HfTC3VmtjRCYW5fgZEgwMae-9bF_MR_KFc9MDO-l1FWKZs0gNpohZd13CvK0qX-I3ivebKshsN6ke-FpY8KDPq9_XknjszVeiCjsYv7oDcEJegdmtC_9OZZ72qy0HcTt1sreP8Q4yB1de7gW7RhMUtCBuJ22A5g9_5KdLc_Ps8XpanEfPYjAUiDWYeNwl5MekMJ8ikV34uTjreV3FJM-NnWf1XE7ePaGNrJ4jB4ZM8Kb9DxxiO7J-gk6tCTzTgya-Pun6MPEAybxdpjEE60nPMMknmOSZ2h5drqYzrApkIELSskGqyCHq5blqVC5Iok2FxPOVUpDrhgDRVOIVKRESsnyJFFxXMocjKlUlqXgPOXkCB3UTS1fII-BClMWJQlZSWhB0kSVsVBRqWIRExWEIzS2u5MVBj1eFzG5yrooBk4yvZ3ZsJ0jdOImfOuBU_4-9Kjbbjcu4nC1EN1xbPc_M8cO5sWRLrYWJHSE3rpuEIr6ny5Ry2bbjYHbM-AMxjzvyeUWJ2ARsFT38B1CugEacH23p67WHfB6EgYsSuOXd_jdV-jhcEyO0cHm-1a-BvV1k7_pGPQ3nQOXBg |
| linkProvider | National Library of Medicine |
| openUrl | ctx_ver=Z39.88-2004&ctx_enc=info%3Aofi%2Fenc%3AUTF-8&rfr_id=info%3Asid%2Fsummon.serialssolutions.com&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=A+Sos+proteomimetic+as+a+pan-Ras+inhibitor&rft.jtitle=Proceedings+of+the+National+Academy+of+Sciences+-+PNAS&rft.au=Hong%2C+Seong+Ho&rft.au=Yoo%2C+Daniel+Y&rft.au=Conway%2C+Louis&rft.au=Richards-Corke%2C+Khyle+C&rft.date=2021-05-04&rft.issn=1091-6490&rft.eissn=1091-6490&rft.volume=118&rft.issue=18&rft_id=info:doi/10.1073%2Fpnas.2101027118&rft.externalDBID=NO_FULL_TEXT |
| thumbnail_l | http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/lc.gif&issn=0027-8424&client=summon |
| thumbnail_m | http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/mc.gif&issn=0027-8424&client=summon |
| thumbnail_s | http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/sc.gif&issn=0027-8424&client=summon |