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Design and synthesis of unprecedented 9- and 10-membered cyclonucleosides with PRMT5 inhibitory activity.
Kawamura, Shuhei; Palte, Rachel L; Kim, Hai-Young; Saurí, Josep; Sondey, Christopher; Mansueto, My S; Altman, Michael D; Machacek, Michelle R.
Affiliation
  • Kawamura S; Discovery Chemistry, Merck & Co., Inc., Boston, MA 02115, United States. Electronic address: shuhei.kawamura@merck.com.
  • Palte RL; Computational and Structural Chemistry, Merck & Co., Inc., Boston, MA 02115, United States.
  • Kim HY; NMR Structure Elucidation, Process and Analytical Chemistry, Merck & Co., Inc., Boston, MA 02115, United States.
  • Saurí J; NMR Structure Elucidation, Process and Analytical Chemistry, Merck & Co., Inc., Boston, MA 02115, United States.
  • Sondey C; Quantitative Biosciences, Merck & Co., Inc., Boston, MA 02115, United States.
  • Mansueto MS; Quantitative Biosciences, Merck & Co., Inc., Boston, MA 02115, United States.
  • Altman MD; Computational and Structural Chemistry, Merck & Co., Inc., Boston, MA 02115, United States.
  • Machacek MR; Discovery Chemistry, Merck & Co., Inc., Boston, MA 02115, United States.
Bioorg Med Chem ; 66: 116820, 2022 07 15.
Article in En | MEDLINE | ID: mdl-35594650
Synthesis of medium-sized rings is known to be challenging due to high transannular strain especially for 9- and 10-membered rings. Herein we report design and synthesis of unprecedented 9- and 10-membered purine 8,5'-cyclonucleosides as the first cyclonucleoside PRMT5 inhibitors. The cocrystal structure of PRMT5:MEP50 in complex with the synthesized 9-membered cyclonucleoside 1 revealed its binding mode in the SAM binding pocket of PRMT5.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Protein-Arginine N-Methyltransferases / Adaptor Proteins, Signal Transducing Language: En Journal: Bioorg Med Chem Journal subject: BIOQUIMICA / QUIMICA Year: 2022 Document type: Article Country of publication: Reino Unido
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Protein-Arginine N-Methyltransferases / Adaptor Proteins, Signal Transducing Language: En Journal: Bioorg Med Chem Journal subject: BIOQUIMICA / QUIMICA Year: 2022 Document type: Article Country of publication: Reino Unido