1. Young Innovators 2009
Prostate-Specific Membrane Antigen (PSMA)-Targeted Imaging, Diagnosis, and Therapy of Prostate Cancer using a PSMA inhibitor as a Homing Ligand
Sumith A. Kularatne
Philip S. Low
Purdue University
Part I

2. Prostate Cancer? Morbidity and Mortality Rates
~230, 000 new cases/ year and ~30, 000 fatalities/ year
Cumulative Cost: 8 – 10 billion dollars/ year
Impacts on Lives: loss mobility, pain, and erectile dysfunction
Inherited

3. Limitations in Current Detection Methods
Digital Rectal Exam (DRE): early detection and metastatic cancer?
Prostate Biopsies: expensive and painful
Prostate Specific Antigen (PSA) test: validity?
Transrectal ultrasound, MRI, and CT scans:
expensive and malignant Vs BPH

4. Limitations in Current Therapies
Radical prostatectomy (surgery)
Radiation therapy
Hormonal therapy: liver damage, cardiovascular disease, weight gain
Chemotherapy: leucopenia, alopecia, nausea, constipation
loss of urinary control
rectal bleeding
impotence
colon & bladder cancer

5. Prostate-Specific Membrane Antigen (PSMA)
Ligand-drug
conjugate
PSMA
Prostate cancer cell

6. Endocytosis NAALADase Activity PCa Cell Ligand PSMA H+ Membrane
Invagination
Nucleus
Ligand
PSMA
PCa Cell
Lysosome
Endosome H+
NAALADase Activity

7. NAALADase/ GCP II Inhibitors
Master et al, EMBO J. 25, (2006)
NAALADase/ GCP II Inhibitors
Jackson et al and Kozikowski et al

8. Superimposition of Docked DUPA with GPI-18431Zn
(a)
(b)
Low, P. S. & Kularatne, S. A.. PCT/WO
Kularatne, S. A., Zhou, Z., Young, J., Post, C. B. & Low, P. S. Mol. Pharm. 2009, 6, 790–800

10. NH-Phe-Glu-Ala-Phe-Phe-CO -4.64 102 8 NH-PEG6-Phe-CO -2.16 338
(d)
(c)
Compound
Peptide spacer (X)
cLog P
KD (nM) 3
None
-3.94
176 4
NH-Glu-Phe-CO
-3.45 60 5
(CH2)8-Phe-Phe-CO
-0.27
13.8 ± 3.9 6
(CH2)8-Phe-Glu-CO
-2.11 31 7
NH-Phe-Glu-Ala-Phe-Phe-CO
-4.64
102 8
NH-PEG6-Phe-CO
-2.16
338
Kularatne, S. A., Zhou, Z., Young, J., Post, C. B. & Low, P. S. Mol. Pharm. 2009, 6, 790–800