2. Academic Validation
  3. Salinization Dramatically Enhance the Anti-Prostate Cancer Efficacies of AR/AR-V7 and Mnk1/2 Molecular Glue Degraders, Galeterone and VNPP433-3β Which Outperform Docetaxel and Enzalutamide in CRPC CWR22Rv1 Xenograft Mouse Model

Salinization Dramatically Enhance the Anti-Prostate Cancer Efficacies of AR/AR-V7 and Mnk1/2 Molecular Glue Degraders, Galeterone and VNPP433-3β Which Outperform Docetaxel and Enzalutamide in CRPC CWR22Rv1 Xenograft Mouse Model

  • Bioorg Chem. 2023 Oct:139:106700. doi: 10.1016/j.bioorg.2023.106700.
Retheesh S Thankan 1,  Elizabeth Thomas 2,  Puranik Purushottamachar 3,  David J Weber 4,  Vincent C O Njar 5
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; Isoprene Pharmaceuticals, Inc. 801 West Baltimore Street, Suite 502J, Baltimore, MD 21201, USA. Electronic address: retheeshst@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. Electronic address: elizabeththomas@som.umaryland.edu.
  • 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; Isoprene Pharmaceuticals, Inc. 801 West Baltimore Street, Suite 502J, Baltimore, MD 21201, USA. Electronic address: PPuranik@som.umaryland.edu.
  • 4 The Center for Biomolecular Therapeutics, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201, USA; Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, 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; Isoprene Pharmaceuticals, Inc. 801 West Baltimore Street, Suite 502J, Baltimore, MD 21201, USA. Electronic address: DWeber@som.umaryland.edu.
  • 5 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; Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, 685 West Baltimore Street, Baltimore, MD 21201, USA; Isoprene Pharmaceuticals, Inc. 801 West Baltimore Street, Suite 502J, Baltimore, MD 21201, USA. Electronic address: vnjar@som.umaryland.edu.
PMID: 37392559 DOI: 10.1016/j.bioorg.2023.106700
Abstract

Galeterone, 3β-(hydroxy)-17-(1H-benzimidazole-1-yl)androsta-5,16-diene (Gal, 1) and VNPP433-3β, 3β-(1H-imidazole-1-yl-17-(1H-benzimidazole-1-yl)androsta-5,16-diene (2) are potent molecular glue degrader modulators of AR/AR-V7 and MNK1/2-eIF4E signaling pathways, and are promising Phase 3 and Phase 1 drug candidates, respectively. Because appropriate salts can be utilized to create new chemical entities with enhanced aqueous solubility, in vivo pharmacokinetics, and enhanced in vitro and in vivo efficacies, the monohydrochloride salt of Gal (3) and the mono- and di-hydrochlorides salts of compound 2, compounds 4 and 5, respectively, were synthesized. The salts were characterized using 1H NMR, 13C NMR and HRMS analyses. Compound 3 displayed enhanced in vitro antiproliferative activity (7.4-fold) against three prostate Cancer cell lines but surprisingly decreased plasma exposure in the pharmacokinetics study. The antiproliferative activities of the compound 2 salts (4 and 5) were equivalent to that of compound 2, but their oral pharmacokinetic profiles were significantly enhanced. Finally, and most importantly, oral administration of the parent compounds (1 and 2) and their corresponding salts (3, 4 and 5) caused dose-dependent potent inhibition/regression of aggressive and difficult-to-treat CWR22Rv1 tumor xenografts growth, with no apparent host toxicities and were highly more efficacious than the blockbuster FDA-approved prostate Cancer drugs, Enzalutamide (Xtandi) and Docetaxel (Taxotere). Thus, the HCl salts of Gal (3) and VNPP433-3β (4 and 5) are excellent orally bioavailable candidates for clinical development.

Keywords

AR/AR-V7 and Mnk1/2 Molecular Glue Degraders; Antitumor efficacy; Castration-resistant prostate cancer (CRPC); Galeterone (Gal); HCl salts; Prostate cancer; VNPP433-3β.

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