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Cyp450 Oc Hc- O Oc)- Ho S US 20090023173A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2009/0023173 A1 Cali et al. (43) Pub. Date: Jan. 22, 2009 (54) LUMINESCENCE-BASED METHODS AND Related U.S. Application Data PROBES FOR MEASURING CYTOCHROME (63) Continuation of application No. 10/665,314, filed on P450 ACTIVITY Sep. 19, 2003. (60) Provisional application No. 60/412.254, filed on Sep. (75) Inventors: James J. Cali, Verona, WI (US); 20, 2002, provisional application No. 60/483,309, Dieter Klaubert, Arroyo Grande, filed on Jun. 27, 2003. CA (US); William Daily, Santa Publication Classification Maria, CA (US); Samuel Kin Sang Ho, New Bedford, MA (US); Susan (51) Int. Cl. CI2O 1/42 (2006.01) Frackman, Madison, WI (US); C07D 277/62 (2006.01) Erika Hawkins, Pembroke (CA); C07D 415/00 (2006.01) Keith V. Wood, Mt. Horeb, WI CI2O I/26 (2006.01) (US) C07D 487/04 (2006.01) (52) U.S. Cl. .............. 435/18: 548/152:544/236: 435/25 Correspondence Address: (57) ABSTRACT SCHWEGMAN, LUNDBERG & WOESSNER, P.A. The invention provides compounds, compositions, methods, P.O. BOX 2938 Substrates, and kits useful for analyzing the metabolic activity MINNEAPOLIS, MN 55402 (US) in cells, tissue, and animals and for Screening test compounds for their effect on cytochrome P450 activity. In particular, a one-step and two-step methods using luminogenic mol (73) Assignee: Promega Corporation, Madison, ecules, e.g. luciferins or coelenterazines, that are cytochrome WI (US) P450 substrates and that are also bioluminescent enzyme, e.g., luciferase, pro-substrates are provided. The present method further provides a method for stabilizing and pro (21) Appl. No.: 12/217,374 longing the luminescent signal in a luciferase-based assay using luciferase stabilizing agents such as reversible (22) Filed: Jul. 3, 2008 luciferase inhibitors. CYP450 luciferase Luciferin- (5- - Luciferin - er-> Light ATP,Mg", ?t Examples 6-O-methyl luciferin--> luciferin- oxyluciferint light or dehydroxyluciferin CYP450 uciferase 6-O-methylluciferin luciferin COOH OOH CYP450 OC HC- O OC)- HO S luciferin dehydroxyluciferin COOH OOH CYP450 O CC H S Patent Application Publication US 2009/0023173 A1 sajdubx=a Patent Application Publication Jan. 22, 2009 Sheet 2 of 27 US 2009/0023173 A1 D-luciferin and D-luciferin derivatives. N NCO2 N COH O CS S N 2 C-S S FC C? Luciferin Luciferin 6' 4-trifluoromethylbenzyl ether (LucTFMBE) N N CO2H N N COH C-S S O CS S Dehydroxyluciferin (Hluc) Luciferin 6' phenylethyl ether (LucPSE) C. y-g r -s-s-s Sy-g S Luciferin 6' methyl ether (LucME) Luciferin 6' gerany ether (LucGE) COH - C Ny-g N-CO2H 1s-o C S X-KS V2 Luciferin 6 ethyl ether Luciferin 6' prenyl ether (LucPE) N N-CO2 JC r Cls-1No C-S S ----,2N Luciferin 6' 2-chloroethyl ether Luciferin 6' 2-picolinyl ether (Luc2PE) (LucCEE) CO2H NN-7 N-COah C y K N1 Luciferin 6' benzyl ether (LucBE) Luciferin 6' 3-picolinyl ether (Luc3PE) N N-CO2 N C W (?7 N -CH2OH N2Cro HO O Sy S Luciferin f' 4-picotinyl ether (LueAPE) ucifero FIG 2 Patent Application Publication Jan. 22, 2009 Sheet 3 of 27 US 2009/0023173 A1 70000 OOOOOO HLuc SOOOOO 2OOOOO 5000 5000 s O Patent Application Publication Jan. 22, 2009 Sheet 4 of 27 US 2009/0023173 A1 50000 40000 30000 20000 10000 7500 5000 g 2500 Patent Application Publication Jan. 22, 2009 Sheet 5 of 27 US 2009/0023173 A1 1000000 LucCEE 500000 100000 50000 O S S S S Š S 30000 LucTFMBE 20000 10000 O s $ $ $ S S S S S is &ss S SS & S. Patent Application Publication Jan. 22, 2009 Sheet 6 of 27 US 2009/0023173 A1 15000 LucPEE FIG, 3G 4OOOOO LucGE 3OOOOO 200000 1OOOOO O S $ $ S S S S S is Patent Application Publication Jan. 22, 2009 Sheet 7 of 27 US 2009/0023173 A1 O LucPEE O 2d O O SS $NS $S SSas SSN SS SS S SY SSN S FIG, 3.I Patent Application Publication Jan. 22, 2009 Sheet 8 of 27 US 2009/0023173 A1 200000 -- A2 LucME -A-2C8 -v- 2C9 -0- CYP450 100000 O 10 20 30 40 50 60 MINUTES FIG, 4A 50000 -- CYP2C9 HLuc 400 -- CYP450 30000 2 20000 10000 O O O 20 30 40 50 60 TO MINUTES 150000 CYP3A4 lucBE -A-CYP450 1OOOOO g SOOOO O O 10 20 30 40 50 60 70 MINUTES FIG, 4C Patent Application Publication Jan. 22, 2009 Sheet 9 of 27 US 2009/0023173 A1 LucME 75000 -- CYP1A2 -A-CYP2C8 -v- CYP2C9 As -0- CYP2B6 -o- CYP2C19 SOOOO -- CYP2D6 -A- CYP2E1 -v- CYP3A4 -O- CYP450 O 60 2O 18O 240 300 MINUTES FIG. 5 Patent Application Publication Jan. 22, 2009 Sheet 10 of 27 US 2009/0023173 A1 30000 LucME 20000 10000 +CYP1A2 O -CYP450 O 250 SOO 750 1000 MINUTES 2000 d 1000 2 +CYP2C8 CYP2C8 O O 250 SOO 750 1000 MINUTES 3000 2000 g 1000 +CYP2C9 CYP450 O O 250 500 750 1000 MINUTES FIG, 6C Patent Application Publication Jan. 22, 2009 Sheet 11 of 27 US 2009/0023173 A1 35 LucME -- CYP2C9 28 -A-CYP450 21 14 7 O O 60 120 18O MINUTES FIG, 7A 100 LucME -H CYP2C8 75 -A- CYP450 50 2.5 00 O 60 120 180 MINUTES FIG. 7B d 2 MINUTES FIG, 7C Patent Application Publication Jan. 22, 2009 Sheet 12 of 27 US 2009/0023173 A1 200 HLuc -- CYP2C9 -A-CYP450 g 100 O 60 120 180 240 300 MINUTES FIG 7D MINUTES FIG 7E Patent Application Publication Jan. 22, 2009 Sheet 13 of 27 US 2009/0023173 A1 LucEE 15OOO 20000 LucME Patent Application Publication Jan. 22, 2009 Sheet 14 of 27 US 2009/0023173 A1 50MLucAPE 50MLuc2PE 75000 5000 50000 4000 25000 2000 O A 1A2 2B6 2D6 2E1 S19 O Al 1A2 2B6 2D6 2E S19 FIG 9A FIG 9B 50 MLuc3PE 50 MPICOLINYLLICIFERINS OOOOO 1000 WITHCYP3A ExSF9 75000 75000 50000 3 50000 25000 25000 SSS 2a2a2 Al A2 2B6 2D6 2E1 S19 O 3-PCOLINYL 2. PCOLINYL 4-PCOLINYL Luc Luc Luc FIG 9C FIG 9D Patent Application Publication Jan. 22, 2009 Sheet 15 of 27 US 2009/0023173 A1 CONVERSION OF CONVERSION OF 6-O-METHYLLCFERINTOLUCFERIN 6-0-CHIOROETHYLLUCIFIERINTO É 0.75 BYHUMANCYP1A2 0.5 LUCIFERINBY HUMANCYP1A1 s s is 0.50 Ér O25 a OOO O O 20 30 40 10 20 30 40 50 60 MINUTES MINUTES FIG, 10B CONVERSION OF CONVERSION OF 6-O-M-PCOLNYLLUCFERINTO DEOXYLECIFERINTOLUCIFERIN 5 OOS LUCIFERINBY HUMANCYP3A4 BYHUMANCYP2C9 S 12 OOS Ée OOS 0.8 5 005 S 0.4 2005 as 2 OOS OO O 10 20 30 40 SO 60 10 20 30 40 50 60 MINUTES MINUTES FIG 10D Patent Application Publication Jan. 22, 2009 Sheet 16 of 27 US 2009/0023173 A1 CYP1A2SMLucME INHIBITIONBYPHENACETIN 75000 IC502225|M 50000 g 25000 O H--- -7 -6 -5 -4 LOGEPHENACETINI(M) FIG 11A CYP1AISLMLucCEE INHIBITIONBYPHENACETIN 24OOOOO H IC502221M 800000 1200000 6OOOOO O H --- .7 -6 .5 -4 LOGPHENACETINI(M) CYP2C918 MHLuc INHIBITION BYDICLOFENAC 7500000 IC50221.3 M SOOOOOO g 2500000 O -7 -6 -5 -4 LOG (DICLOFENACI(M) FIG, IIC Patent Application Publication Jan. 22, 2009 Sheet 17 of 27 US 2009/0023173 A1 2500 2000 1500 1000 500 O FIG, 12A FIG, 12B Patent Application Publication Jan. 22, 2009 Sheet 18 of 27 US 2009/0023173 A1 FIG, 12C THONI(ÍTOH FIG, 12D Patent Application Publication Jan. 22, 2009 Sheet 19 of 27 US 2009/0023173 A1 12000 FIG, 12E FIG, 12F Patent Application Publication Jan. 22, 2009 Sheet 20 of 27 US 2009/0023173 A1 FIG, 12G {{SWTHONI(ITOJ FIG 12H Patent Application Publication Jan. 22, 2009 Sheet 21 of 27 US 2009/0023173 A1 FIG, 12I {SWTHONI(ITOH FIG, 12J Patent Application Publication Jan. 22, 2009 Sheet 22 of 27 US 2009/0023173 A1 OOOOO FIG, 12K {SWTHONICITOH FIG, 12L Patent Application Publication Jan. 22, 2009 Sheet 23 of 27 US 2009/0023173 A1 0009 OOOZ Patent Application Publication Jan. 22, 2009 Sheet 24 of 27 US 2009/0023173 A1 99:|| 29:0 82:000:0 0009 000|| Patent Application Publication Jan. 22, 2009 Sheet 26 of 27 US 2009/0023173 A1 LUCFERN-CEE LUCIFERIN-CEE (MEDIUM) 150000 (LYSATES) 28OOOO 100000 g 21 OOOO 140000 50000 TOOOO O S S' SS FIG, 16B LUCIFERIN-BE LUCFERIN-BE 15OOOO (MEDIUM) (LYSATES) OOOOO P 2 SOOOO FIG, 16C FIG, 16D Patent Application Publication Jan. 22, 2009 Sheet 27 of 27 US 2009/0023173 A1 STABILIZATION OFLUMNESCENTCYP1A1 SIGNAL 15OOOOO WITH APMBT AND AMBT -- 50 MAMBT -o- 50 MAPMBT OOOOOO -V- O 500000 40000 2OOOO MINUTES FIG, 17 US 2009/00231 73 A1 Jan. 22, 2009 LUMNESCENCE-BASED METHODS AND reduces the bioavailablity of the compound, lowering effi PROBES FOR MEASURING CYTOCHROME cacy. This family of genes and the polymorphisms within the P450 ACTIVITY family play important roles in the interindividual variation in drug metabolism, occurrence and severity of side effects and CROSS-REFERENCE TO RELATED therapeutic failures. APPLICATIONS 0006 Hundreds of cytochrome P450s have been identified in diverse organisms including bacteria, fungi, plants, and 0001. This application is a continuation of U.S. patent animals (18). All CYP450s use a heme cofactor and share application Ser. No. 10/665,314, filed Sep. 19, 2003, which Structural attributes. Most CYP450s are 400 to 530 amino application claims the benefit of the filing date of U.S. Appli acids in length. The secondary structure of the enzyme is cation Ser. No. 60/412.254, filed Sep. 20, 2002, the disclo about 70% alpha-helical and about 22% beta-sheet.
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