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VNPP433-3β
- Development stage
- Preclinical
- Lead developer
- University of Maryland School of Medicine
- Modality
- Molecular Glues → Targeted Protein Degraders (TPDs) → Small Molecules
- Administration
- Oral
01
Overview
VNPP433-3β is a next-generation galeterone analog and an orally active molecular glue degrader that targets the androgen receptor (AR), its splice variants (AR-Vs, including AR-V7), and MAP kinase-interacting serine/threonine protein kinases Mnk1/2. It promotes proteasomal degradation of full-length AR and AR-V7 by enhancing their interaction with E3 ligases MDM2/CHIP while disrupting AR-HSP90 binding. This leads to decreased transcriptional activity of AR-responsive oncogenes, inhibition of prostate cancer stem cells by downregulating epithelial–mesenchymal transition and stem cell markers, and disruption of mRNA translation initiation via depletion of MNK1/2 and phosphorylated eIF4E. VNPP433-3β induces apoptosis, inhibits cell cycle progression, tumor growth in castration-resistant prostate cancer (CRPC) models in vitro and in vivo, including resistant human prostate cancer cell lines. It is being developed primarily for treatment of prostate cancer including CRPC.
- Other names
- next generation galeterone analogNGGA
02
Targets
AR (Adrenergic receptors)MKNK2 (MAP kinase-interacting serine/threonine-protein kinase 2)AR-V7 (Androgen Receptor Variant 7)MKNK1 (Mitogen‑activated protein kinase‑interacting serine/threonine-protein kinase 1)
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