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  1. Article ; Online: Pan-KRAS inhibitor disables oncogenic signalling and tumour growth.

    Kim, Dongsung / Herdeis, Lorenz / Rudolph, Dorothea / Zhao, Yulei / Böttcher, Jark / Vides, Alberto / Ayala-Santos, Carlos I / Pourfarjam, Yasin / Cuevas-Navarro, Antonio / Xue, Jenny Y / Mantoulidis, Andreas / Bröker, Joachim / Wunberg, Tobias / Schaaf, Otmar / Popow, Johannes / Wolkerstorfer, Bernhard / Kropatsch, Katrin Gabriele / Qu, Rui / de Stanchina, Elisa /
    Sang, Ben / Li, Chuanchuan / McConnell, Darryl B / Kraut, Norbert / Lito, Piro

    Nature

    2023  Volume 619, Issue 7968, Page(s) 160–166

    Abstract: KRAS is one of the most commonly mutated proteins in cancer, and efforts to directly inhibit its function have been continuing for decades. The most successful of these has been the development of covalent allele-specific inhibitors that trap KRAS G12C ... ...

    Abstract KRAS is one of the most commonly mutated proteins in cancer, and efforts to directly inhibit its function have been continuing for decades. The most successful of these has been the development of covalent allele-specific inhibitors that trap KRAS G12C in its inactive conformation and suppress tumour growth in patients
    MeSH term(s) Animals ; Mice ; Body Weight ; Enzyme Activation ; Mutation ; Neoplasms/drug therapy ; Neoplasms/genetics ; Neoplasms/pathology ; Nucleotides/metabolism ; Proto-Oncogene Proteins p21(ras)/antagonists & inhibitors ; Proto-Oncogene Proteins p21(ras)/genetics ; Proto-Oncogene Proteins p21(ras)/metabolism ; Signal Transduction/drug effects ; Cell Division/drug effects ; Substrate Specificity
    Chemical Substances Hras protein, mouse (EC 3.6.5.2) ; Nras protein, mouse (EC 3.6.5.2) ; Nucleotides ; Proto-Oncogene Proteins p21(ras) (EC 3.6.5.2)
    Language English
    Publishing date 2023-05-31
    Publishing country England
    Document type Journal Article
    ZDB-ID 120714-3
    ISSN 1476-4687 ; 0028-0836
    ISSN (online) 1476-4687
    ISSN 0028-0836
    DOI 10.1038/s41586-023-06123-3
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Fragment Optimization of Reversible Binding to the Switch II Pocket on KRAS Leads to a Potent, In Vivo Active KRAS

    Bröker, Joachim / Waterson, Alex G / Smethurst, Chris / Kessler, Dirk / Böttcher, Jark / Mayer, Moriz / Gmaschitz, Gerhard / Phan, Jason / Little, Andrew / Abbott, Jason R / Sun, Qi / Gmachl, Michael / Rudolph, Dorothea / Arnhof, Heribert / Rumpel, Klaus / Savarese, Fabio / Gerstberger, Thomas / Mischerikow, Nikolai / Treu, Matthias /
    Herdeis, Lorenz / Wunberg, Tobias / Gollner, Andreas / Weinstabl, Harald / Mantoulidis, Andreas / Krämer, Oliver / McConnell, Darryl B / W Fesik, Stephen

    Journal of medicinal chemistry

    2022  Volume 65, Issue 21, Page(s) 14614–14629

    Abstract: Activating mutations in KRAS are the most frequent oncogenic alterations in cancer. The oncogenic hotspot position 12, located at the lip of the switch II pocket, offers a covalent attachment point for ... ...

    Abstract Activating mutations in KRAS are the most frequent oncogenic alterations in cancer. The oncogenic hotspot position 12, located at the lip of the switch II pocket, offers a covalent attachment point for KRAS
    MeSH term(s) Humans ; Proto-Oncogene Proteins p21(ras)/genetics ; Genes, ras ; Mutation ; Neoplasms/genetics ; Cysteine
    Chemical Substances Proto-Oncogene Proteins p21(ras) (EC 3.6.5.2) ; Cysteine (K848JZ4886) ; KRAS protein, human
    Language English
    Publishing date 2022-10-27
    Publishing country United States
    Document type Journal Article ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
    ZDB-ID 218133-2
    ISSN 1520-4804 ; 0022-2623
    ISSN (online) 1520-4804
    ISSN 0022-2623
    DOI 10.1021/acs.jmedchem.2c01120
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Targeted Synthesis of Complex Spiro[3H-indole-3,2'-pyrrolidin]-2(1H)-ones by Intramolecular Cyclization of Azomethine Ylides: Highly Potent MDM2-p53 Inhibitors.

    Gollner, Andreas / Weinstabl, Harald / Fuchs, Julian E / Rudolph, Dorothea / Garavel, Geraldine / Hofbauer, Karin S / Karolyi-Oezguer, Jale / Gmaschitz, Gerhard / Hela, Wolfgang / Kerres, Nina / Grondal, Elisabeth / Werni, Patrick / Ramharter, Juergen / Broeker, Joachim / McConnell, Darryl B

    ChemMedChem

    2018  Volume 14, Issue 1, Page(s) 88–93

    Abstract: Mouse double minute 2 (MDM2) is a main and direct inhibitor of the crucial tumor suppressor p53. Reports from initial clinical trials showed that blocking this interaction with a small-molecule inhibitor can have great value in the treatment of cancer ... ...

    Abstract Mouse double minute 2 (MDM2) is a main and direct inhibitor of the crucial tumor suppressor p53. Reports from initial clinical trials showed that blocking this interaction with a small-molecule inhibitor can have great value in the treatment of cancer for patients with p53 wild-type tumors; however, it also revealed dose-limiting hematological toxicities and drug-induced resistance as main issues. To overcome the former, an inhibitor with superior potency and pharmacokinetic properties to ultimately achieve full efficacy with less-frequent dosing schedules is required. Toward this aim, we optimized our recently reported spiro-oxindole inhibitors by focusing on the crucial interaction with the amino acid side chain of His96
    MeSH term(s) Animals ; Azo Compounds/chemistry ; Azo Compounds/pharmacology ; Cell Line, Tumor ; Crystallography, X-Ray ; Cyclization ; Density Functional Theory ; Dose-Response Relationship, Drug ; Humans ; Indoles/chemical synthesis ; Indoles/chemistry ; Indoles/pharmacology ; Mice ; Models, Molecular ; Molecular Structure ; Proto-Oncogene Proteins c-mdm2/antagonists & inhibitors ; Proto-Oncogene Proteins c-mdm2/chemistry ; Proto-Oncogene Proteins c-mdm2/metabolism ; Pyrrolidinones/chemical synthesis ; Pyrrolidinones/chemistry ; Pyrrolidinones/pharmacology ; Spiro Compounds/chemical synthesis ; Spiro Compounds/chemistry ; Spiro Compounds/pharmacology ; Structure-Activity Relationship ; Thiosemicarbazones/chemistry ; Thiosemicarbazones/pharmacology ; Tumor Suppressor Protein p53/antagonists & inhibitors ; Tumor Suppressor Protein p53/chemistry ; Tumor Suppressor Protein p53/metabolism
    Chemical Substances Azo Compounds ; Indoles ; Pyrrolidinones ; Spiro Compounds ; Thiosemicarbazones ; Tumor Suppressor Protein p53 ; azomethine ; spiro(3H-indole-3,2'-pyrrolidin)-2(1H)-one ; Proto-Oncogene Proteins c-mdm2 (EC 2.3.2.27)
    Language English
    Publishing date 2018-12-11
    Publishing country Germany
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2218496-X
    ISSN 1860-7187 ; 1860-7179
    ISSN (online) 1860-7187
    ISSN 1860-7179
    DOI 10.1002/cmdc.201800617
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: Discovery of quinazolines as histamine H4 receptor inverse agonists using a scaffold hopping approach.

    Smits, Rogier A / de Esch, Iwan J P / Zuiderveld, Obbe P / Broeker, Joachim / Sansuk, Kamonchanok / Guaita, Elena / Coruzzi, Gabriella / Adami, Maristella / Haaksma, Eric / Leurs, Rob

    Journal of medicinal chemistry

    2008  Volume 51, Issue 24, Page(s) 7855–7865

    Abstract: From a series of small fragments that was designed to probe the histamine H(4) receptor (H(4)R), we previously described quinoxaline-containing fragments that were grown into high affinity H(4)R ligands in a process that was guided by pharmacophore ... ...

    Abstract From a series of small fragments that was designed to probe the histamine H(4) receptor (H(4)R), we previously described quinoxaline-containing fragments that were grown into high affinity H(4)R ligands in a process that was guided by pharmacophore modeling. With a scaffold hopping exercise and using the same in silico models, we now report the identification and optimization of a series of quinazoline-containing H(4)R compounds. This approach led to the discovery of 6-chloro-N-(furan-3-ylmethyl)2-(4-methylpiperazin-1-yl)quinazolin-4-amine (VUF10499, 54) and 6-chloro-2-(4-methylpiperazin-1-yl)-N-(thiophen-2-ylmethyl)quinazolin-4-amine (VUF10497, 55) as potent human H(4)R inverse agonists (pK(i) = 8.12 and 7.57, respectively). Interestingly, both compounds also possess considerable affinity for the human histamine H(1) receptor (H(1)R) and therefore represent a novel class of dual action H(1)R/H(4)R ligands, a profile that potentially leads to added therapeutic benefit. Compounds from this novel series of quinazolines are antagonists at the rat H(4)R and were found to possess anti-inflammatory properties in vivo in the rat.
    MeSH term(s) Animals ; Anti-Inflammatory Agents/chemistry ; Chemistry, Pharmaceutical/methods ; Drug Design ; Histamine Agonists/chemistry ; Humans ; Hydrogen-Ion Concentration ; Inhibitory Concentration 50 ; Kinetics ; Models, Chemical ; Models, Molecular ; Molecular Conformation ; Quinazolines/chemistry ; Rats ; Receptors, G-Protein-Coupled/agonists ; Receptors, Histamine ; Receptors, Histamine H4
    Chemical Substances Anti-Inflammatory Agents ; HRH4 protein, human ; Histamine Agonists ; Quinazolines ; Receptors, G-Protein-Coupled ; Receptors, Histamine ; Receptors, Histamine H4
    Language English
    Publishing date 2008-12-25
    Publishing country United States
    Document type Journal Article
    ZDB-ID 218133-2
    ISSN 1520-4804 ; 0022-2623
    ISSN (online) 1520-4804
    ISSN 0022-2623
    DOI 10.1021/jm800876b
    Database MEDical Literature Analysis and Retrieval System OnLINE

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