Direct-to-biology, automated, nano-scale synthesis, and phenotypic screening-enabled E3 ligase modulator discovery

Autor: Zefeng Wang, Shabnam Shaabani, Xiang Gao, Yuen Lam Dora Ng, Valeriia Sapozhnikova, Philipp Mertins, Jan Krönke, Alexander Dömling

Publikováno v: Nature Communications, Vol 14, Iss 1, Pp 1-12 (2023)

Abstract Thalidomide and its analogs are molecular glues (MGs) that lead to targeted ubiquitination and degradation of key cancer proteins via the cereblon (CRBN) E3 ligase. Here, we develop a direct-to-biology (D2B) approach for accelerated discover

Externí odkaz: https://doaj.org/article/f92198598a504265983f5dc2bc34f074

Proteomic profiling reveals CDK6 upregulation as a targetable resistance mechanism for lenalidomide in multiple myeloma

Autor: Yuen Lam Dora Ng, Evelyn Ramberger, Stephan R. Bohl, Anna Dolnik, Christian Steinebach, Theresia Conrad, Sina Müller, Oliver Popp, Miriam Kull, Mohamed Haji, Michael Gütschow, Hartmut Döhner, Wolfgang Walther, Ulrich Keller, Lars Bullinger, Philipp Mertins, Jan Krönke

Publikováno v: Nature Communications, Vol 13, Iss 1, Pp 1-13 (2022)

Acquired resistance to immunomodulatory drugs is common in multiple myeloma patients, but rarely attributed to genetic alterations. Here, proteomic, phosphoproteomic and RNA sequencing analysis in five paired pre-treatment and relapse samples reveals

Externí odkaz: https://doaj.org/article/d4504678ee754ca4b1b981178e24fb56

Heterobifunctional ligase recruiters enable pan-degradation of inhibitor of apoptosis proteins

Autor: Yuen Lam Dora Ng, Aleša Bricelj, Jacqueline A. Jansen, Arunima Murgai, Kirsten Peter, Katherine A. Donovan, Michael Gütschow, Jan Krönke, Christian Steinebach, Izidor Sosič

Publikováno v: Journal of medicinal chemistry, vol. 66, no. 7, pp. 4703-4733, 2023.
Journal of medicinal chemistry, str. 4703-4733 : Ilustr., Vol. 66, iss. 7, 2023
COBISS-ID: 512806681

Proteolysis targeting chimeras (PROTACs) represent a new pharmacological modality to inactivate disease-causing proteins. PROTACs operate via recruiting E3 ubiquitin ligases, which enable the transfer of ubiquitin tags onto their target proteins, lea

Externí odkaz: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::4e25f1087502a057345c9d203428b453
https://hdl.handle.net/20.500.12556/RUL-145892

SUMOylation inhibition overcomes proteasome inhibitor resistance in multiple myeloma

Autor: Guus J. J. E. Heynen, Francis Baumgartner, Michael Heider, Upayan Patra, Maximilian Holz, Jan Braune, Melanie Kaiser, Isabell Schäffer, Stefanos A. Bamopoulos, Evelyn Ramberger, Arunima Murgai, Yuen Lam Dora Ng, Uta Margareta Demel, Dominik Laue, Sven Liebig, Josefine Krüger, Martin Janz, Axel Nogai, Markus Schick, Philipp Mertins, Stefan Müller, Florian Bassermann, Jan Krönke, Ulrich Keller, Matthias Wirth

Publikováno v: Blood Advances

Proteasome inhibition is a highly effective treatment for multiple myeloma (MM). However, virtually all patients develop proteasome inhibitor resistance, which is associated with a poor prognosis. Hyperactive small ubiquitin-like modifier (SUMO) sign

Externí odkaz: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::62e3785fe11be986954c96a6487cb6c9
http://edoc.mdc-berlin.de/21976/2/21976suppl.zip

Influence of Linker Attachment Points on the Stability and Neosubstrate Degradation of Cereblon Ligands

Autor: Marius Monschke, Sina Müller, Jan Krönke, Izidor Sosič, Michael Gütschow, Dominic Ferber, Aleša Bricelj, Christian Steinebach, Yuen Lam Dora Ng, Karl G. Wagner, Robert Kuchta

Publikováno v: ACS Med Chem Lett

[Image: see text] Proteolysis targeting chimeras (PROTACs) hijacking the cereblon (CRBN) E3 ubiquitin ligase have emerged as a novel paradigm in drug development. Herein we found that linker attachment points of CRBN ligands highly affect their aqueo

Externí odkaz: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::0dc13fd34d1d549e06c0b71cf90a1c24
https://doi.org/10.1021/acsmedchemlett.1c00368