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(12) Patent Application Publication (10) Pub. No.: US 2015/0119330 A1 Mcgee Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2015/0119330 A1 Mcgee Et Al US 2015O1 19330A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2015/0119330 A1 McGee et al. (43) Pub. Date: Apr. 30, 2015 (54) SUBSTRATES AND INHIBITORS OF PROLYL Publication Classification OLGOPEPTIDASE AND FIBROBLAST ACTIVATION PROTEIN AND METHODS OF (51) Int. Cl. USE C07K 7/06 (2006.01) (71) Applicant: The Board of Regents of the University C07K5/II (2006.01) of Oklahoma, Norman, OK (US) C07K5/09 (2006.01) (52) U.S. Cl. (72) Inventors: Patrick A. McGee, Oklahoma City, OK CPC ................. C07K 7/06 (2013.01); C07K5/0817 (US); Kenneth W. Jackson, Edmond, OK (US); Victoria J. Christiansen, (2013.01); C07K5/1019 (2013.01) Oklahoma City, OK (US) (21) Appl. No.: 14/398,886 (57) ABSTRACT (22) PCT Filed: May 3, 2013 Inhibitors of fibroblast activation protein alpha (FAP) and (86). PCT No.: PCT/US2013/0395.43 Prolyl Oligopeptidase (POP) are disclosed, along with their S371 (c)(1), use in various therapies related to conditions, diseases, and (2) Date: Nov. 4, 2014 disorders involving abnormal cell proliferation Such as malig nancies and angiogenesis, and in neural disorders such as Related U.S. Application Data Alzheimer's disease. Stalk portions of the inhibitor mol (60) Provisional application No. 61/643,001, filed on May ecules, and substrates of FAP and POP, are also disclosed and 4, 2012, provisional application No. 61/793,183, filed may be used, for example, in screening methods for identify on Mar. 15, 2013. ing Such inhibitors. 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Patent Application Publication Apr. 30, 2015 Sheet 6 of 11 US 201S/O119330 A1 A Cells on plastic 400 -H Control -- M831OuM & J941 OuM : -- POP Activity 0-8-i-us-------------. & 6 8 10 12 14 16 18 20 Time (hrs) Cells on Matrigel 400 --Control M831OLM “&“J941OLM 300- l r POP - & Activity s &: -- ^ & FAP & -1 . m m Activity 0 &-i-S$.3s-Sax8--------ax&s1 0 2 4 6 8 10 12 14, 16 18 2 Time (hrs) Figure 6 Patent Application Publication Apr. 30, 2015 Sheet 7 of 11 US 201S/O119330 A1 A 1 O O 8 O 6 O 40 o WI38 MCF 12A HMVECO Cell Type B S. E O s ce S, a a 3 o o SN S N 38 3 & 555 & 3 kDa as s > S S E E 100-8 in in six 75 a 50 Patent Application Publication Apr. 30, 2015 Sheet 8 of 11 US 201S/O119330 A1 OW dod {{SOAO ojoso Ao ? eue CueN eubuqueW eleSA |e. eyesAeo. OSN dod : : & 9) x ins * O 2 : &. s y s su al Patent Application Publication Apr. 30, 2015 Sheet 9 of 11 US 201S/O119330 A1 Rs' ssss w SSS 8. x &xxxxxxxxxxxxxxxxxxxxx : X & SS SNS NyS. sas s &x swww.www.www.www.www.www.s. Xs &s S. sSKXs say s SaaS & saxxxxxxxxxxxxxxxxxxssssssssssssssssssssss s sar a. w Sas SS X NY s SS sar SS s & S wsS& SY SSX SS SS wSXSS Sass S ass Sixx Sas * S. s S. & &ss s w &S s 8xx Sw Sassas s & sxxx xx S X S\s & s ss & S& & & & &ss Sws x SS sy YS s a\\\\\\\\\\\SSSSSSSSSSSSSSSSSSSSSSSSSSSSssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssss'S W 1. s s & S S y S & SSY &y as S. xx & syas S&Sx - N SS&x w s S$ &\s sr. wers Patent Application Publication Apr. 30, 2015 Sheet 10 of 11 US 201S/O119330 A1 s: Figure 10A Figure 10B Patent Application Publication Apr. 30, 2015 Sheet 11 of 11 US 201S/O119330 A1 HCT116 Colon Cancer Xenografts in Mice-Treatment with J94 and M83 Tumor Volume versus Days of treatment 4000 ^Contro YJ94-50 ^M33-50 3600 3200 O mirretty OD 3: 7D 1OD 18D 2AD 28D Treatment day FIGURE 11 US 2015/01 19330 A1 Apr. 30, 2015 SUBSTRATES AND INHIBITORS OF PROLYL genetic deletion or pharmacologic inhibition of FAP by OLGOPEPTIDASE AND FIBROBLAST glutamyl-proline boronic acid (Glu-boroPro) decreased stro ACTIVATION PROTEIN AND METHODS OF mal growth in mouse models of lung and colon cancer. How USE ever, Glu-boroPro has an exceptionally short plasma half-life before cyclizing and losing inhibitory activity 22. More CROSS-REFERENCE TO RELATED over, it also inhibits dipeptidyl peptidase IV (DPPIV), which APPLICATIONS/INCORPORATION BY is important in plasma glucose regulation and immune func REFERENCE STATEMENT tion 23. Hence, despite inhibiting FAP and suppressing 0001. The present application claims the benefit under 35 tumor growth, Glu-boroPro is not likely to be therapeutically U.S.C. 119(e) of U.S. Provisional Application Ser. No. useful in cancer 24. 61/643,001, filed May 4, 2012, and U.S. Provisional Appli 0006. The measurement of cellular FAP activity and inhi cation Ser. No. 61/793,183, filed Mar. 15, 2013. The entire bition is confounded by another prolyl endopeptidase: contents of each of the above-referenced applications are namely, Prolyl Oligopeptidase (POP) which is elevated in hereby expressly incorporated herein by reference. many cancers 25. POP is a prolyl-specific serine protein ases, which cleaves peptides of less than about 30 amino acids STATEMENT REGARDING FEDERALLY in length. The enzyme is present in most tissues, but is noted to be more abundant in selected organs, e.g., brain and kidney. SPONSORED RESEARCH ORDEVELOPMENT Recently POP has been indicated as making secondary cleav 0002 This invention was made with government support ages of thymosin-B4 to yield the derivative peptide, acetyl under Contract Number W81XWH-081-0588 awarded by the serine-asparagine-lysine-proline, which appears to be a Department of Defense (DOD) and Contract Number potent stimulator of angiogenesis 26. Both FAP and POP HL072995 awarded by the National Institutes of Health activities are commonly measured using non-specific Sub (NIH). The government has certain rights in the invention. strates such as Z-Gly-Pro-AMC or succinyl-Gly-Pro-AMC, neither of which distinguishes between the two activities BACKGROUND 27. Consequently, total prolyl-specific endopeptidase activ 0003 C-Antiplasmin (CAP) is a glycoprotein in blood ity, which is often attributed to FAP alone, may also include plasma that rapidly and specifically inhibits the enzyme, plas POP activity. This complicates interpretations about the min, which digests blood clots, whether presenting early as effects of inhibiting either enzyme on cancer growth. Pre intravascular platelet-fibrin deposits or as partially or com clinical studies have suggested other promising applications pletely occlusive thrombi. Similarly, plasmin and CAP of POP inhibition for managing memory, learning disorders activities are important to the development and survival of and depression, but development of relatively benign, highly fibrinas occurs in inflammation, wound healing and virtually effective POP inhibitors for in vivo testing have been elusive. all forms of cancer and its metastases. Human a-antiplasmin The results, newly described herein, indicate that POP is (CAP), also known as C-plasmin inhibitor, is the main expressed in significant amounts by a variety of cancer cells inhibitor of plasmin. Plasmin plays a critical role in fibrin grown in culture. proteolysis and tissue remodeling. The inventors discovered 0007 Certain compounds which specifically inhibit either antiplasmin-cleaving enzyme (APCE) in human plasma and one or both of FAP and POP and therefore can be used to treat showed that it is a soluble isoform or derivative of fibroblast various conditions which involve these proteins are desirable. activation protein-alpha (FAP). Like APCE, FAP is also a Thus, the presently disclosed and claimed inventive concept prolyl-specific enzyme that exhibits both endopeptidase and (s) is directed to, but not limited to, substrates and inhibitors dipeptidyl peptidase activities. of FAP and/or POP, and to methods of using FAP and/or POP 0004 FAP significantly over-expresses in >90% of epithe inhibitors for treating conditions such as but not limited to, lial-derived cancers 1-3. FAP is produced transiently by cancers, neural disorders, and angiogenesis, and to Screening activated Stromal fibroblasts during embryogenesis 4 and methods for identifying such inhibitors, that overcome the wound healing 3, but other than an occasional normal fibro disadvantages and defects of the prior art. blast or pancreatic islet C.-cell, it is not expressed by normal adult tissues or benign tumors 2, 3, 5). FAP is prominent on BRIEF DESCRIPTION OF THE DRAWINGS the membranes of proliferating fibroblasts in diseases where 0008 FIG. 1 is a characterization of FAP and POP in fibrous tissue growth is a conspicuous feature, such as pri fibroblasts. Panel A. Confocal images of permeabilized mary pulmonary fibrosis 6; chronic hepatitis 7; certain WI-38 and VA-13 fibroblasts grown on plastic slides and bone-associated malignancies 8, 9; and the arthritides 10. labeled with mouse anti-FAP mab F19 followed by anti Selected parenchymatous cancer cells may also occasionally mouse-AlexaFluor 568 (red) and the DNA stain DAPI express FAP11. (green). Panel B. FAP and POP activities offibroblasts grown 0005 While a biologic substrate for the proteinase activity on plastic wells as measured by cleavage of a fluorescent of FAP has not been definitively established, results indicate substrate designated as “C95” (acetyl-Arg-AEEA-Gly-Pro that FAP helps digest extracellular matrix (ECM) compo AMC), and using a POP specific inhibitor compound desig nents as tissue is remodeled to accommodate cancer expan nated as “J94 (acetyl-Lys-Leu-Arg-(L)boroPro) to separate sion 2, 16, 17.
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