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Young Innovators 2009

Explore PSMA inhibitor as a homing ligand in targeting prostate cancer for imaging, diagnosis, and therapy. Developed potent therapeutic agents, located primary/metastatic disease, monitored therapy response, and more. Acknowledgements to collaborators and funding sources.

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Young Innovators 2009

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  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 III

  2. Design of PSMA-Targeted Chemotherapeutic Agents IC50 = 1 nM (to LNCaP cell) Low, P. S. & Kularatne, S. A. PCT/WO2009026177 IC50 = 0.8 nM (to LNCaP cells)

  3. Relative Binding Affinity of DUPA-TubH for LNCaP Cells + 100 nM DUPA-99mTc Relative affinity ~ 0.27 DUPA-TubH

  4. LC-MS Analysis of Disulfide Carbonate Mediated Drug Release DTT = Dithiothreitol DUPA-TubH t = 0 min DTT DUPA-Linker t =60 min DUPA-TubH

  5. Potency of DUPA-TubH to LNCaP Cells in Culture Competition with excess PMPA DUPA-TubH Kularatne, S. A., Wang, K., Santhapuram, H-K. R. & Low, P. S. Mol Pharm. 2009, 6, 780-789

  6. Effects of DUPA-TubH I on Growth of LNCaP Tumors DUPA-TubH I

  7. Pathological Analysis of DUPA-TubH I Treated Mice Saline Treated DUPA-TubH I Treated H & E (Hemotaxylin and Eosin) stain (400 x) NL – no lesion identified Kularatne, S. A., Subramanian, B., van Alstine, W.& Low, P. S. (unpublished data)

  8. Conclusions • Developed PSMA-targeted imaging agents • Locate primary and metastatic disease • Detect CTCs in blood samples of prostate cancer patients • Monitor response to therapy • Detect disease recurrence following surgery • Select patients for subsequent DUPA-targeted chemotherapy (B) Developed highly potent PSMA-targeted therapeutic agents (C) Developed Folate-targeted PET imaging and immunotherapeutic agents

  9. Acknowledgements Prof. Philip S. Low Prof. Philip L. Fuchs Prof. Ei-chi Negishi Prof. Hilkka I. Kenttämaa Collaborators: Dr. Z. Zhou (Purdue) Dr. C. Post (Purdue) Dr. W. Alstine (Purdue) Dr. W. He (Purdue) Dr. L. Hartmann (Mayo Clinic) Dr. G. Klee (Mayo Clinic) Dr. K. Wang (Endocyte Inc) Dr. H-K. Santhapuram (Endocyte Inc) Dr. R. Amato (The Methodist Hospital, TX) Dr. Paul McQuade (Merck Research Laboratories, PA) Special Thanks: Group members Funding: Endocyte Inc, West Lafayette Department of Chemistry, Purdue University

  10. References • Ghosh A, Heston, WDJ. Cell Biochem. 2004, 91, 528-539. • Mesters JR, Barinka C, Li W. EMBO J. 2006, 25, 1375-1384. • Kozikowski AP, Zhang J, Nan FJ. Med. Chem. 2004, 47, 1729-1738. • Jackson PF, Slusher BS. Curr. Med. Chem. 2001; 8, 949-957 • 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 • Kularatne, S. A., Wang, K., Santhapuram, H-K. R. & Low, P. S. Mol. Pharm. 6, 781-790 • Slusher, B.S. et al J. Comp. Neurol. 315, 217-229 • Ghosh, A. et al Cell. Biochem. 91, 528-539 • Sodee, D.B. et al The Prostate 37, 140-148 • Thomas, M. A. ;Kularatne, S. A., et. Al. Ann. N.Y. Acad. Sci. 2009, 1175: 32–3 • Low, P. S., Wei, H. & Kularatne, S. A. PCT/WO2008057437 • He, W., Kularatne, S. A., et. al. Int. J. Cancer, 2008, 123, 1968-1973 • Kularatne, S. A., Chelvam V., Low P. S. et al. (Manuscript in submission • Kularatne, S. A., Subramanian, B., van Alstine, W.& Low, P. S. (unpublished data) Young Innovators 2009

  11. BIOS/Contact info Born in Kandy, Sri Lanka, Sumith A. Kularatne graduated from the University of Peradeniya, Sri Lanka, with a B.S. (honors) in the Chemistry Honors program. He earned a master’s degree in organic chemistry from Wichita State University, Kansas, conducting research on synthesis of endo-[n.m.n.m] (n,m ≥ 3) metacyclophanes using Cu(I)-catalyzed cross-coupling/ Grignard system and elucidating of solvent effects in anion binding selectivity and stoichiometry of synthetic anion binding receptors using tri- & tetra-urea picket porphyrins as model systems (supramolecular chemistry). Sumith then earned a Ph.D. in organic/medicinal chemistry from Purdue University in October 2009, conducting research on receptor-mediated drug delivery using small molecular ligands for treatment of cancer and inflammatory diseases under the guidance of Ralph C. Corley Distinguished Professor Philip S. Low. Based on his current research work, he is an inventor on 5 pending patents and a co-author of 10 peer reviewed publications, 2 book chapters, and 12 proceedings/ paper presentations in meetings. He will be working with Prof. Peter G. Shultz at Scripps Research Institute, San Diego for his postdoctoral fellowship from November 2009. Young Innovators 2009

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