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

9

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