Результаты исследований: Научные публикации в периодических изданиях › статья › Рецензирование
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 изданиях › статья › Рецензирование
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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