Novel deuterated Mnk1/2 protein degrader VNLG-152R analogs: Synthesis, In vitro Anti-TNBC activities and pharmacokinetics in mice

Eur J Med Chem. 2022 Aug 5;238:114441. doi: 10.1016/j.ejmech.2022.114441. Epub 2022 May 14.


A new and improved synthesis of lead Mnk1/2 protein degrader, VNLG-152R, 4-(±)-(1H-imidazole-1-yl)-N-(4-fluorophenyl)-(E)-retinamide (1) has been developed from commercially available 4-oxo-ATRA (8). This procedure was also utilized to synthesize the seven possible deuterated analogs of compound 1 (11-17). The deuterated analogs were either better or equipotent to 1 in in vitro antiproliferative activities against MDA-MB-231 and MDA-MB-468 human TNBC cells. The Mnk1/2 degraders were equally effective as a standard TNBC therapy (paclitaxel). Importantly, the expression of Mnk1, peIF4E and their associated downstream targets, including cyclin D1 and Bcl2, were strongly decreased in compound 1/analogs (11-17)-treated TNBC cells signifying inhibition of Mnk1-eIF4E signaling. More importantly, we showed that deuterated analogs, 12, 16 and 17 possess improved pharmacokinetics parameters following oral administration to CD-1 female mice compared to the parent non-deuterated compound 1, thus addressing the rapid clearance (short half-life and short residence time) pharmacokinetic inadequacy of compound 1.

Keywords: Mnk1/2 degraders; Pharmacokinetics; TNBC therapeutics; VNLG-152R deuteration.

MeSH terms

  • Animals
  • Eukaryotic Initiation Factor-4E / metabolism
  • Female
  • Humans
  • Mice
  • Paclitaxel
  • Protein Serine-Threonine Kinases / metabolism*
  • Signal Transduction
  • Triple Negative Breast Neoplasms*


  • Eukaryotic Initiation Factor-4E
  • Mknk1 protein, mouse
  • Mknk2 protein, mouse
  • Protein Serine-Threonine Kinases
  • Paclitaxel