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

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.
Puranik Purushottamachar 1,  Elizabeth Thomas 2,  Retheesh S Thankan 3,  Vincent C O Njar 4
Affiliations

Affiliations

  • 1 Department of Pharmacology, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD, 21201, USA; The Center for Biomolecular Therapeutics, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD, 21201, USA. Electronic address: PPuranik@som.umaryland.edu.
  • 2 Department of Pharmacology, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD, 21201, USA; The Center for Biomolecular Therapeutics, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD, 21201, USA.
  • 3 Department of Pharmacology, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD, 21201, USA; The Center for Biomolecular Therapeutics, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD, 21201, USA; Flavocure Biotech, 701 E. Pratt Street, Suite 2033, Baltimore, MD, 21202, USA; Isoprene Pharmaceuticals, Inc, 875 Hollins Street, Suite 102D, Baltimore, MD, 21201, USA.
  • 4 Department of Pharmacology, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD, 21201, USA; The Center for Biomolecular Therapeutics, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD, 21201, USA; Isoprene Pharmaceuticals, Inc, 875 Hollins Street, Suite 102D, Baltimore, MD, 21201, USA; Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD, 21201, USA. Electronic address: VNjar@som.umaryland.edu.
PMID: 35617854 DOI: 10.1016/j.ejmech.2022.114441
Abstract

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.

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