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

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

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

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

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

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

NAALADase/ GCP II Inhibitors Master et al, EMBO J. 25, 1375-1384 (2006) NAALADase/ GCP II Inhibitors Jackson et al and Kozikowski et al

Superimposition of Docked DUPA with GPI-18431 Zn (a) (b) Low, P. S. & Kularatne, S. A.. PCT/WO2009026177 Kularatne, S. A., Zhou, Z., Young, J., Post, C. B. & Low, P. S. Mol. Pharm. 2009, 6, 790–800

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