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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. KularatnePhilip S. Low
Purdue University
Part I
ONH
O
HOHN O
HONH
ONH
N
OH
OH
Department of Chemistry
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
2
ONH
O
HOHN O
HONH
ONH
N
OH
OH
Department of Chemistry
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
3
ONH
O
HOHN O
HONH
ONH
N
OH
OH
Department of Chemistry
Limitations in Current Therapies
• Radical prostatectomy (surgery)
• Radiation therapy
• Hormonal therapy: liver damage, cardiovascular disease, weight gain
• Chemotherapy: leucopenia, alopecia, nausea, constipation
4
loss of urinary controlrectal bleedingimpotencecolon & bladder cancer
ONH
O
HOHN O
HONH
ONH
N
OH
OH
Department of Chemistry
Prostate-Specific Membrane Antigen (PSMA)
5
Ligand-drug conjugate
PSMA
Prostate cancer cell
ONH
O
HOHN O
HONH
ONH
N
OH
OH
Department of Chemistry
6
H+
H+
H+
MembraneInvagination
Nucleus
Ligand
PSMA
PCa Cell
H+
H+
H+
H+
H+
H+
LysosomeH+
H+
H+
Endosome
NAALADase Activity
NH
OCO2
-
HN
O
CO2-
CO2-
NH
OCO2
- +H3N
O
CO2-
CO2-
O-NAALADase /GCP II
N-acetylaspartylglutamate(NAAG)
Neurotransmitter
N-acetylaspartate(NAAG)
GlutamateNeurotransmitter
Endocytosis
H+
ONH
O
HOHN O
HONH
ONH
N
OH
OH
Department of Chemistry
NAALADase/ GCP II Inhibitors
7Jackson et al and Kozikowski et al
COOHNH
NH
HOOC
O
COOH
H H
COOH
COOHP
HO
OCOOH
OH
KI = 2 uM KI = 700 nM
KI = 3 nM
COOHNH
NH
HOOC
O
H H
COOHHO
OHP
HO
O
OH
KI = 10 uM
COOHNH
NH
O
COOH
H H
COOH
NHN
N N
COOHP
HO
O
OH
KI = 8 nM KI = 335 nM
COOHP
O
COOH
OHHOOC
H
KI = 1 nM
NH
NH
O
COOHH
COOH
HOOC
S
H
KI = 29 nM
COOHP
HO
O
COOH
OH
KI = 0.3 nMPMPA
COOHP
HO
O
OH
KI = 185 nM
COOH
COOHP
O
COOH
OH H
KI = 560 nM
COOHP
HOOC
O
COOH
OH
KI = 2 nM
H H H
HH
COOHP
O
COOH
OH H
I
KI = 30 nMGPI-184312-[3-(1,3-Dicarboxy propyl)
-Ureido] Pentanedioic Acid (DUPA)
Master et al, EMBO J. 25, 1375-1384 (2006)
ONH
O
HOHN O
HONH
ONH
N
OH
OH
Department of Chemistry
Superimposition of Docked DUPA with GPI-18431
8
K699
R210
E425
H377
D387
D453
R534
Zn
(a) (b)
NH
NH
O
COOHH
COOH
HOOCH
COOH
KI = 8 nMDUPA
COOHP
O
COOH
OH H
I
KI = 30 nMGPI-18431Low, 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
ONH
O
HOHN O
HONH
ONH
N
OH
OH
Department of Chemistry
10
(d)(c)
N
NH2
O N
O
S
COOHNH
NH
HOOC
O
COOHO H
N
H H
COOH99mTc
O
X
HOOC
DUPA
Imaging moiety
Kularatne, S. A., Zhou, Z., Young, J., Post, C. B. & Low, P. S. Mol. Pharm. 2009, 6, 790–800
Compound Peptide spacer (X) cLog P KD (nM)3 None -3.94 1764 NH-Glu-Phe-CO -3.45 605 (CH2)8-Phe-Phe-CO -0.27 13.8 ± 3.96 (CH2)8-Phe-Glu-CO -2.11 317 NH-Phe-Glu-Ala-Phe-Phe-CO -4.64 1028 NH-PEG6-Phe-CO -2.16 338