YOUNG INNOVATORS 2009 ProstateSpecific Membrane Antigen PSMATargeted Imaging
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
Department of Chemistry Design of PSMA-Targeted Chemotherapeutic Agents IC 50 = 1 n. M (to LNCa. P cell) 2 Low, P. S. & Kularatne, S. A. PCT/WO 2009026177 IC 50 = 0. 8 n. M (to LNCa. P cells)
Department of Chemistry Relative Binding Affinity of DUPA-Tub. H for LNCa. P Cells + 100 n. M DUPA-99 m. Tc Relative affinity ~ 0. 27 3 DUPA-Tub. H
Department of Chemistry LC-MS Analysis of Disulfide Carbonate Mediated Drug Release DUPA-Tub. H DTT = Dithiothreitol t = 0 min DTT DUPA-Linker t =60 min DUPA-Tub. H 4
Department of Chemistry Potency of DUPA-Tub. H to LNCa. P Cells in Culture Competition with excess PMPA DUPA-Tub. H Kularatne, S. A. , Wang, K. , Santhapuram, H-K. R. & Low, P. S. Mol Pharm. 2009, 6, 780 -789 5
Department of Chemistry Effects of DUPA-Tub. H I on Growth of LNCa. P Tumors DUPA-Tub. H I 6
Department of Chemistry Pathological Analysis of DUPA-Tub. H I Treated Mice Saline Treated DUPA-Tub. H I Treated Treatment Group Saline xs PMPA + DUPA-Tub. H I H & E (Hemotaxylin and Eosin) stain (400 x) Treatment Group Saline xs PMPA + DUPA-Tub. H I Liver Kidney Spleen Lung % of tumor dead mass < 10 % > 95% NL – no lesion identified Heart Muscle Intestine Skin NL NL Bone marrow NL NL minor NL NL NL 7 Kularatne, S. A. , Subramanian, B. , van Alstine, W. & Low, P. S. (unpublished data)
Department of Chemistry Conclusions (A)Developed PSMA-targeted imaging agents 1) Locate primary and metastatic disease 2) Detect CTCs in blood samples of prostate cancer patients 3) Monitor response to therapy 4) Detect disease recurrence following surgery 5) Select patients for subsequent DUPA-targeted chemotherapy (B) Developed highly potent PSMA-targeted therapeutic agents (C) Developed Folate-targeted PET imaging and immunotherapeutic agents 8
Department of Chemistry 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 Mc. Quade (Merck Research Laboratories, PA) Special Thanks: Group members Funding: Endocyte Inc, West Lafayette Department of Chemistry, Purdue University 9
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/WO 2009026177 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/WO 2008057437 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
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 ≥ 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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