USRE46129E1 - Dimeric small molecule potentiators of apoptosis - Google Patents
Dimeric small molecule potentiators of apoptosis Download PDFInfo
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- USRE46129E1 USRE46129E1 US14/152,870 US201414152870A USRE46129E US RE46129 E1 USRE46129 E1 US RE46129E1 US 201414152870 A US201414152870 A US 201414152870A US RE46129 E USRE46129 E US RE46129E
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Classifications
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- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing aromatic rings
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- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
- C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
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Abstract
Description
- Liu et al, Structural basis for binding of Smac/DIABLO to the XIAP BIR3 domain; Nature 2000 Dec. 21-28; 408(6815): 1004-8.
- Wu et al., Structural basis of IAP recognition by Smac/DIABLO; Nature 2000 Dec. 21-28; 408(6815):1008-12.
- Fesik, et al., Peptides derived from smac (DIABLO) and methods of using them to screen for apoptosis modulating compounds; WO 2002030959.
- McLendon, et al., IAP binding peptides and assays for identifying compounds that bind IAP; WO 2002096930.
- Shi, Compositions and methods for regulating apoptosis; WO 2002026775.
- Debatin, et al., Smac-peptides as therapeutics against cancer and autoimmune diseases by sensitizing for TRAIL- or anticancer drug-induced apoptosis; WO 2003086470.
- Alnemri, Conserved sequence of XIAP-binding motif in human caspase-9 and Smac/DIABLO and therapeutic uses for screening modulators of apoptosis; WO 2003010184.
- Arnt et al., Synthetic Smac/DIABLO peptides enhance the effects of chemotherapeutic agents by binding XIAP and cIAP1 in situ; J Biol. Chem. 2002 Nov. 15; 277(46):44236-43. Epub 2002 Sep. 5.
- IAP binding peptide or polypeptide and methods of using the same; US Pat Publ No. 20020132786.
- US Pat Publ No. 20020160975, Conserved XIAP-interaction motif in caspase-9 and Smac/DIABLO for mediating apoptosis.
- US Pat Publ No. 20020177557, Compositions and method for regulating apoptosis.
- U.S. Pat. No. 6,608,026, Wang, et al., Apoptotic Compounds;
- Li et al., Targeting and amplification of immune killing of tumor cells by pro-Smac, Int J Cancer. 2004 March 10; 109(1):85-94.
wherein:
R1 and R1′ are selected from hydrogen, optionally substituted methyl, and hydroxyl;
R2 and R2′ are selected from optionally substituted methyl and optionally substituted ethyl;
R3 and R3′ are selected from CH2, NH, O and S;
R4 and R4′ are selected from CH and N;
R5-R8, and R5′-R8′ are selected from hydrogen, optionally hetero-, optionally substituted alkyl, optionally hetero-, optionally substituted alkenyl, optionally hetero-, optionally substituted alkynyl, optionally hetero-, optionally substituted aryl; and
L is a linker covalently linking R2, R5, R6 or R7, with R2′, R5′, R6′ or R7′,
or a pharmaceutically-acceptable salt thereof.
including all combinations wherein:
R1 and R1′ are selected from hydrogen, optionally substituted methyl, and hydroxyl;
R2 and R2′ are selected from optionally substituted methyl and optionally substituted ethyl;
R3 and R3′ are selected from CH2, NH, O and S;
R4 and R4′ are selected from CH and N;
R5-R8, and R5′-R8′ are selected from hydrogen, optionally hetero-, optionally substituted alkyl, optionally hetero-, optionally substituted alkenyl, optionally hetero-, optionally substituted alkynyl, optionally hetero-, optionally substituted aryl; and
L is a linker covalently linking R2, R5, R6 or R7, with R2′, R5′, R6′ or R7′,
or a pharmaceutically-acceptable salt thereof.
TABLE 1 |
Capsule Formulations |
Formula 1 | Formula 2 | Formula 3 | Formula 4 | |
Capsule | mg/ | mg/ | mg/ | mg/ |
Formulation | capsule | capsule | capsule | capsule |
Mimetic (Solid Solution) | 100 | 400 | 400 | 200 |
Silicon Dioxide | 0.625 | 2.5 | 3.75 | 1.875 |
Magnesium Stearate NF2 | 0.125 | 0.5 | 0.125 | 0.625 |
Croscarmellose Sodium | 11.000 | 44.0 | 40.0 | 20.0 |
NF | ||||
Pluronic F68 NF | 6.250 | 25.0 | 50.0 | 25.0 |
Silicon Dioxide NF | 0.625 | 2.5 | 3.75 | 1.875 |
Magnesium Stearate NF | 0.125 | 0.5 | 1.25 | 0.625 |
Total | 118.750 | 475.00 | 475.00 | 475.00 |
Capsule Size | No. 4 | No. 0 | No. 0 | No. 2 |
Preparation of Solid Solution
- 1. Add 90 microliters of mimetic/BIR2,3 mixture to each well of a 96-well microtiter plate.
- 2. Add 10 microliters of test compound per well.
- 3. Shake 5 min and within 5 minutes determine amount of fluorescence polarization by using a Fluorolite FPM-2 Fluorescence Polarization Microtiter System (Dynatech Laboratories, Inc).
Tested mimetics significantly and specifically bind the IAP BIR2,3 domain.
3. High Throughput Solid Phase Mimetic-BIR2,3 Binding/Binding-Interference Assay.
A. Reagents:- Neutralite Avidin: 20 μg/ml in PBS.
- Blocking buffer: 5% BSA, 0.5% Tween 20 in PBS; 1 hour at room temperature.
- Assay Buffer: 100 mM KCl, 20 mM HEPES pH 7.6, 1 mM MgCl2, 1% glycerol, 0.5% NP-40, 50 mM b-mercapto-ethanol, 1 mg/ml BSA, cocktail of protease inhibitors.
- 33P mimetic 10× stock: 10−8-10−6M “cold” mimetic supplemented with 200,000-250,000 cpm of labeled mimetic (Beckman counter). Place in the 4° C. microfridge during screening.
- Protease inhibitor cocktail (1000×): 10 mg Trypsin Inhibitor (BMB #109894), 10 mg Aprotinin (BMB #236624), 25 mg Benzamidine (Sigma # B-6506), 25 mg Leupeptin (BMB #1017128), 10 mg APMSF (BMB #917575), and 2 mM NaVO3 (Sigma # S-6508) in 10 ml of PBS.
- BIR2,3: 10−7-10−5M biotinylated BIR2,3 domain (supra) in PBS.
B. Preparation of Assay Plates: - Coat with 120 μl of stock N-Avidin per well overnight at 4° C.
- Wash 2 times with 200 μl PBS.
- Block with 150 μl of blocking buffer.
- Wash 2 times with 200 μl PBS.C.
C. Assay: - Add 40 μl assay buffer/well.
- Add 10 μl compound or extract.
- Add 10 μl 33P-mimetic (20-25,000 cpm/0.1-10 pmoles/well=10−9-10−7M final conc)
- Shake at 25° C. for 15 minutes.
- Incubate additional 45 minutes at 25° C.
- Add 40 μM biotinylated BIR2,3 (0.1-10 pmoles/40 ul in assay buffer)
- Incubate 1 hour at room temperature.
- Stop the reaction by washing 4 times with 200 μM PBS.
- Add 150 μM scintillation cocktail.
- Count in Topcount.
D. Controls for all Assays (Located on Each Plate):
- 1. Lumma, W. C.; Wohl, Ronald A. Eur. Pat. Appl. 1985, EP 134424 A1
- 2. Bejjani, J; Chemla, F; Audouin, M. J. Org. Chem., 2003, 68, 9747-9752.
- 3. Black, Julian; Brown, Alan D; Erizabet C L; Smith, J D; Mckelloy, A B. 2000 JP 2000063380
- 4. Dininno, F; Guthikonda, R N.; Schmitt, S M. 1994 U.S. Pat. No. 5,292,879 A
43a-t is synthesized according to similar procedures as above described for 60 using treatment with propargyl bromide and Ag2O in Et2O, followed by standard work-up procedures.
61 is synthesized according to similar procedures as described above for 18 using Cu(OAc)2 in CH3CN.
Claims (35)
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CA2582734C (en) | 2011-05-03 |
US7638544B2 (en) | 2009-12-29 |
WO2005084317A3 (en) | 2006-01-12 |
US20110124585A1 (en) | 2011-05-26 |
JP2007526321A (en) | 2007-09-13 |
US20090281155A1 (en) | 2009-11-12 |
EP1723122A2 (en) | 2006-11-22 |
US20050197403A1 (en) | 2005-09-08 |
EP1723122A4 (en) | 2009-11-25 |
AU2005218555B2 (en) | 2008-01-03 |
US8143418B2 (en) | 2012-03-27 |
JP4674231B2 (en) | 2011-04-20 |
US7309792B2 (en) | 2007-12-18 |
US7816538B2 (en) | 2010-10-19 |
US20090312379A1 (en) | 2009-12-17 |
US7884211B2 (en) | 2011-02-08 |
AU2005218555A1 (en) | 2005-09-15 |
CA2582734A1 (en) | 2005-09-15 |
CN1926118A (en) | 2007-03-07 |
EP1723122B1 (en) | 2014-11-19 |
US20080119532A1 (en) | 2008-05-22 |
WO2005084317A2 (en) | 2005-09-15 |
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