What is PTUPB?
PTUPB is a dual COX-2/soluble epoxide hydrolase (sEH) inhibitor that has demonstrated novel activity as an AKR1C3 inhibitor, showing synergistic effects with enzalutamide in treating castration-resistant prostate cancer by blocking AR/AR-V7 signaling pathways. 1
Mechanism of Action
PTUPB functions through multiple pathways that are particularly relevant to advanced prostate cancer:
AKR1C3 inhibition: PTUPB suppresses AKR1C3 activity more effectively than traditional COX-2 inhibitors like indomethacin and celecoxib, which is critical because AKR1C3 is a steroidogenic enzyme frequently elevated in castration-resistant prostate cancer (CRPC) 1
AR/AR-V7 axis blockade: The drug targets the AKR1C3/AR-V7 complex, which is recognized as a major driver of drug resistance in advanced prostate cancer 1
Dual COX-2/sEH inhibition: Beyond its prostate cancer applications, PTUPB inhibits both cyclooxygenase-2 and soluble epoxide hydrolase, providing anti-tumor activity with organ-protective effects 2
Clinical Relevance in Prostate Cancer
PTUPB demonstrates particular value in overcoming enzalutamide resistance:
The combination of PTUPB with enzalutamide provides superior tumor suppression compared to enzalutamide alone by blocking both AR and AR-V7 signaling pathways 1
This combination inhibits growth of castration-relapsed VCaP xenograft tumors and patient-derived xenograft organoids, addressing a critical unmet need in CRPC treatment 1
PTUPB suppresses CRPC cell growth more effectively than conventional COX-2 inhibitors, suggesting it has unique properties beyond standard anti-inflammatory agents 1
Mechanism of Resistance Targeting
The drug addresses key resistance mechanisms in advanced prostate cancer:
AR-V7 targeting: AR variant 7 (AR-V7) is a truncated androgen receptor that lacks the ligand-binding domain, making it constitutively active and resistant to conventional AR inhibitors like enzalutamide 1, 3
Reciprocal regulation: AKR1C3 levels are reciprocally regulated by full-length AR through binding to the distal enhancer region of the AKR1C3 gene, creating a feedback loop that PTUPB disrupts 1
Broader Anti-Cancer Properties
PTUPB has demonstrated efficacy beyond prostate cancer:
In bladder cancer models, PTUPB potentiated cisplatin-based therapy, resulting in significantly reduced tumor growth and prolonged survival without increasing toxicity 2
The drug increases apoptosis and decreases phosphorylation in MAPK/ERK and PI3K/AKT/mTOR pathways when combined with chemotherapy 2
PTUPB is highly active in vivo by inhibiting angiogenesis, contributing to its anti-tumor effects 2
Current Status
PTUPB remains an investigational agent not yet approved for clinical use. The evidence supporting its use comes from preclinical studies demonstrating synergistic effects with enzalutamide in CRPC models 1. While no clinical guidelines currently recommend PTUPB, the preclinical data suggest it may represent a promising strategy for targeting the AKR1C3/AR/AR-V7 axis to overcome drug resistance to AR signaling inhibitors in advanced prostate cancer 1.