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Synthesis of novel glutarimide ligands for the E3 ligase substrate receptor Cereblon (CRBN) : Investigation of their binding mode and antiproliferative effects against myeloma cell lines. / Krasavin, Mikhail; Adamchik, Maria; Bubyrev, Andrey; Heim, Christopher; Maiwald, Samuel; Zhukovsky, Daniil; Zhmurov, Petr; Bunev, Alexander; Hartmann, Marcus D.

в: European Journal of Medicinal Chemistry, Том 246, 114990, 15.01.2023.

Результаты исследований: Научные публикации в периодических изданияхстатьяРецензирование

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@article{9923026ab81a4db09d8736c3b1a4425d,
title = "Synthesis of novel glutarimide ligands for the E3 ligase substrate receptor Cereblon (CRBN): Investigation of their binding mode and antiproliferative effects against myeloma cell lines",
abstract = "To expand the chemical toolkit for targeted protein degradation, we report the generation of a new series of non-thalidomide Cereblon (CRBN) ligands. Readily available 2-methylidene glutarimide was converted to a series of 2-((hetero)aryl(methyl))thio glutarimides via the thio-Michael addition reaction. The compounds thus synthesized were evaluated for their affinity to the thalidomide-binding domain of human CRBN and their binding modes studied via X-ray crystallography. This helped identify several promising glutarimide derivatives which bind stronger to CRBN compared to thalidomide and contain a functional group which permits further chemical conjugation. Oxidation of the sulfur atom in a select group of 2-((hetero)aryl(methyl))thio glutarimides produced the respective sulfones which were found to possess a markedly stronger antiproliferative profile against multiple myeloma cell lines and a sophisticated structural binding mode with additional hydrogen bonding interactions. The newly identified Cereblon ligands form the basis for the synthesis of novel PROTAC protein degraders.",
keywords = "Cereblon, IMiDs, Molecular glue, New ligand space, PROTAC, Thio-Michael addition, Humans, Peptide Hydrolases/metabolism, Adaptor Proteins, Signal Transducing/metabolism, Ubiquitin-Protein Ligases/metabolism, Proteolysis, Cell Line, Tumor, Multiple Myeloma/drug therapy, Thalidomide",
author = "Mikhail Krasavin and Maria Adamchik and Andrey Bubyrev and Christopher Heim and Samuel Maiwald and Daniil Zhukovsky and Petr Zhmurov and Alexander Bunev and Hartmann, {Marcus D.}",
note = "Publisher Copyright: {\textcopyright} 2022 Elsevier Masson SAS",
year = "2023",
month = jan,
day = "15",
doi = "10.1016/j.ejmech.2022.114990",
language = "English",
volume = "246",
journal = "European Journal of Medicinal Chemistry",
issn = "0223-5234",
publisher = "Elsevier",

}

RIS

TY - JOUR

T1 - Synthesis of novel glutarimide ligands for the E3 ligase substrate receptor Cereblon (CRBN)

T2 - Investigation of their binding mode and antiproliferative effects against myeloma cell lines

AU - Krasavin, Mikhail

AU - Adamchik, Maria

AU - Bubyrev, Andrey

AU - Heim, Christopher

AU - Maiwald, Samuel

AU - Zhukovsky, Daniil

AU - Zhmurov, Petr

AU - Bunev, Alexander

AU - Hartmann, Marcus D.

N1 - Publisher Copyright: © 2022 Elsevier Masson SAS

PY - 2023/1/15

Y1 - 2023/1/15

N2 - To expand the chemical toolkit for targeted protein degradation, we report the generation of a new series of non-thalidomide Cereblon (CRBN) ligands. Readily available 2-methylidene glutarimide was converted to a series of 2-((hetero)aryl(methyl))thio glutarimides via the thio-Michael addition reaction. The compounds thus synthesized were evaluated for their affinity to the thalidomide-binding domain of human CRBN and their binding modes studied via X-ray crystallography. This helped identify several promising glutarimide derivatives which bind stronger to CRBN compared to thalidomide and contain a functional group which permits further chemical conjugation. Oxidation of the sulfur atom in a select group of 2-((hetero)aryl(methyl))thio glutarimides produced the respective sulfones which were found to possess a markedly stronger antiproliferative profile against multiple myeloma cell lines and a sophisticated structural binding mode with additional hydrogen bonding interactions. The newly identified Cereblon ligands form the basis for the synthesis of novel PROTAC protein degraders.

AB - To expand the chemical toolkit for targeted protein degradation, we report the generation of a new series of non-thalidomide Cereblon (CRBN) ligands. Readily available 2-methylidene glutarimide was converted to a series of 2-((hetero)aryl(methyl))thio glutarimides via the thio-Michael addition reaction. The compounds thus synthesized were evaluated for their affinity to the thalidomide-binding domain of human CRBN and their binding modes studied via X-ray crystallography. This helped identify several promising glutarimide derivatives which bind stronger to CRBN compared to thalidomide and contain a functional group which permits further chemical conjugation. Oxidation of the sulfur atom in a select group of 2-((hetero)aryl(methyl))thio glutarimides produced the respective sulfones which were found to possess a markedly stronger antiproliferative profile against multiple myeloma cell lines and a sophisticated structural binding mode with additional hydrogen bonding interactions. The newly identified Cereblon ligands form the basis for the synthesis of novel PROTAC protein degraders.

KW - Cereblon

KW - IMiDs

KW - Molecular glue

KW - New ligand space

KW - PROTAC

KW - Thio-Michael addition

KW - Humans

KW - Peptide Hydrolases/metabolism

KW - Adaptor Proteins, Signal Transducing/metabolism

KW - Ubiquitin-Protein Ligases/metabolism

KW - Proteolysis

KW - Cell Line, Tumor

KW - Multiple Myeloma/drug therapy

KW - Thalidomide

UR - http://www.scopus.com/inward/record.url?scp=85143606368&partnerID=8YFLogxK

U2 - 10.1016/j.ejmech.2022.114990

DO - 10.1016/j.ejmech.2022.114990

M3 - Article

C2 - 36476642

AN - SCOPUS:85143606368

VL - 246

JO - European Journal of Medicinal Chemistry

JF - European Journal of Medicinal Chemistry

SN - 0223-5234

M1 - 114990

ER -

ID: 101522380