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US 2012/0070404 A1 Hausheer (43) Pub US 20120070404A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2012/0070404 A1 Hausheer (43) Pub. Date: Mar. 22, 2012 (54) INCREASING CANCER PATIENTSURVIVAL (52) U.S. Cl. ...................... 424/85.2: 424/94.1: 514/19.3: TIME BY ADMINISTRATION OF 424/141.1; 424/130.1; 424/649; 424/94.6: DTHO-CONTAINING COMPOUNDS 424/133.1: 514/266.4: 514/9.7; 424/85.4: 424/94.3: 568/22 (75) Inventor: Frederick H. Hausheer, Boerne, (57) ABSTRACT TX (US) The present invention discloses and claims compositions, (73) Assignee: BioNumerik Pharmaceuticals, methods of treatment, and kits which cause an increase in the time of Survival in cancer patients, wherein the cancer: (i) Inc. overexpresses thioredoxin or glutaredoxin and/or (ii) exhibits evidence of thioredoxin- or glutaredoxin-mediated resistance (21) Appl. No.: 12/807,931 to one or more chemotherapeutic interventions. The present invention also discloses and claims methods and kits for the (22) Filed: Sep. 16, 2010 administration of said compositions to properly treat cancer patients. Additionally, the present invention discloses and Publication Classification claims methods and kits for quantitatively determining the (51) Int. Cl. level of expression of thioredoxin or glutaredoxin in the can C07C32L/4 (2006.01) cer cells of a cancer patient, methods of using those deter A6 IK 38/02 (2006.01) mined levels in the initial diagnosis and/or planning of Sub A6 IK 38/16 (2006.01) sequent treatment methodologies for said cancer patient, as A 6LX 39/395 (2006.01) well as ascertaining the potential growth “aggressiveness” of A6 IK 38/20 (2006.01) the particular cancer and treatment responsiveness of the A6 IK 33/24 (2006.01) particular type of cancer. Further, the present invention dis A6 IK 38/50 (2006.01) closes and claims novel pharmaceutical compositions, meth A 6LX 3/57 (2006.01) ods, and kits used for the treatment of patients with medical A6 IK 38/22 (2006.01) conditions and disease where there is the overexpression of A6 IK 38/2 (2006.01) thioredoxin and/or glutaredoxin, and wherein this overex A6 IK 38/43 (2006.01) pression is associated with deleterious physiological effects A6IP35/00 (2006.01) in the patients. Apoptosis, Inhibited Cell Growth, Decreased DNA Synthesis Oxidized Gutatione - - -Glutaredoxin - - - - - - - Mesna Reductase es Glutathiole Glutathione Disulfide 7 N (GSH) s Tavocept or NADPH NADP+ - D S Tavocept Metabolite (GR)GR SH Reduced -- Glutepdoxin. - - Reduction of Stabilization, Anti-Apoptosis protein or low Activation or Effects y molecular weight Reduction of Deglutathionylation disulfides Transcription of protein glutathione bonds e.g., regulates Blocks NFB, NF1 Akt redox state Akti HO/PP2A “s PKC PKA (inhibits mediated Apoptosis; Ribonucleotide PTP-1B disulfide formation) Reductase PEBPIRUNX Activation of TNF-cNFK-B Blocks antiapoptotic Inhibition of signaling pathways Binding regulation cytochrome C V Deoxyribonucleotide DNA release and synthesis Transcription Signal transduction GSKAP-1 CE. via TRAF2, xta MEKK3, Proliferation via DNA signaling pathways; KK proteins; Synthesis and Transcription Repair control Blocks ASKSEKf NKAMEKK mediated Apoptosis Patent Application Publication Mar. 22, 2012 Sheet 1 of 15 US 2012/0070404 A1 Fig. 1 Apoptosis, Inhibited Cell Growth, Decreased DNA Synthesis ---4-----(a) Oxidized L Glutaredoxin Gutathione - - - - - - - - - - Mesna Reductase - Glutathione Glutathionel 1 Disulfide (GSH) Tavocept or NADPH NADP+ GR) SHT Tavocept Metabolite GR N-1 SH Reduced - Glutaredoxin Reduction of Stabilization, Anti-Apoptosis protein or low Activation or Effects molecular weight Reduction of Deglutathionylation disulfides Transcription of protein Factors glutathione bonds e.g., regulates Blocks NFkB NF1 Akt redox state Akt/HO/PP2A -9-y PKC PKA (inhibits mediated Apoptosis; Ribonucleotide PTP-1B disulfide formation) Reductase m Activation of TNF-oNFK-B Blocks - 1 a antiapoptotic Akt Inhibition of signaling pathways cytochrome C Deoxyribonucleotide region release and synthesis 9 cardiolipin oxidation Proliferation via signaling pathways; IKK proteins; Synthesis and Transcription Repair control Bocks ASK/SEK/ JNK/MEKK7 mediated Apoptosis Patent Application Publication Mar. 22, 2012 Sheet 2 of 15 US 2012/0070404 A1 Fig. 2 The Coupled Glutaredoxin/GSH/Glutathione Reductase System GSSG (glutathione disulfide) NADPH GR H' NADP+ . y \ . (Gr) (Gra)- Reduced Grx xidized Grx H' XSH + YSH X-SS-Y can be low molecular weight disulfides, protein disulfides, and Formula (I) compounds Patent Application Publication Mar. 22, 2012 Sheet 3 of 15 US 2012/0070404 A1 Fig. 3 Apoptosis, Inhibited Cell Growth, Decreased DNA Synthesis txi Oxidized Thioredoxin NADPH Nigedoxina as e o e to e o 0 e o os e sao s-> Mesna 41 Reductase VT - - - - Tavocept or NADP . so o so ea o oo e o e o oo e o Tavocept Metabolite OwisaR: "e ds w ea d i Reduction of Protein Stabilization or Disulfide Bonds. Activation of Transcription r e. (e.g., Sir Ribonucleotide e-9-2 OXOS Binding to Reductase p53 Ref g ASK1 HIF1o PKC (inhibits kinase cytokines Blocks Proper cell redox balance; p38 MAPK, JNK, Reduction in signals via Caspases, B.D. Reactive Oxygen Species signaling mediated Apoptosis (free radicals and peroxides) pathways. Growth Patent Application Publication Mar. 22, 2012 Sheet 4 of 15 US 2012/0070404 A1 Fig. 4 Reduction of small disulfides by TXR Reduction of thioredoxin (TX) by TXR NADPH NADP" w NADPH NADP" XR S XR S X-SS-Y +H" XSH -- YSH NS The coupled TX/TXR system NADPH NADP SH >< ts 0< (x) X-SS - Y -Y^- XSH +YSH X-SS-Y may include various Formula (I) compounds of the present invention. Patent Application Publication Mar. 22, 2012 Sheet 5 of 15 US 2012/0070404 A1 Jo30.130(I uu0p30.]] S‘??I |16||I9Igsr8S?N?|Osa |16||I&?opowiazosto |---|-||0|? Patent Application Publication Mar. 22, 2012 Sheet 6 of 15 US 2012/0070404 A1 9nIBA-AI 9áà (pol?10.JNGIGIÐ)ÒNGI—Qu?odpu??Kubu?u? I043BÃIU[080IJO?SºL 3.Ienbs-??O|Jo93.139CI so?s?e?suI0p03.J. ? J040B(I Patent Application Publication US 2012/0070404 A1 (†1?uponeuæH-ÎORIu?qoßou^H)qu?odpu??KuepuooºS |16||0ILILE92|LºllaNg1?poolvulah IT-TITETETETT Patent Application Publication Mar. 22, 2012 Sheet 8 of 15 US 2012/0070404 A1 |0,5||0?No.t? _6'Iº||09189ILBLIN? (oni)aamiuuooi?o?oipunluºpuedepui as||vs?| |0|| 10130G| - Patent Application Publication Mar. 22, 2012 Sheet 9 of 15 US 2012/0070404 A1 IeA?A.InS-Qu?odpu?IÁIepu009S (Kep)?eA?AunS IBAIAInSue?pòIN ?ep86;:L8LLINA 00600800100900900700900Z,001 eel eaenuino Patent Application Publication Mar. 22, 2012 Sheet 10 of 15 US 2012/0070404 A1 pºdoSu30:18/ANEI+ 006008001009009 __<!--------+++.---*****----- 008 002 001 eqe eAAunS 9Agenuino Patent Application Publication Mar. 22, 2012 Sheet 11 of 15 US 2012/0070404 A1 pºuOSu,90:L8LLIN?+ *;*******. II(?!) 00600800100900900ý00800Z0010 ee eAA InSeAlenun)(t.£:::::::…………………………………………………-…-…………………………………-…-- Patent Application Publication Mar. 22, 2012 Sheet 13 of 15 US 2012/0070404 A1 Fig. 13 Overall Survival (OS) and Progression-free Survival (PFS) Patients Events Median in Months 1-Year Survival Rates O (%) Arm (n) (n) (95% C.I.) (95% C.I.) TAVNo 76 74 5.5sey (4.3Tea - 6.9)Vol. - 9.2saf (4.1s. - 17.0)R. A. O. TAV 75 70 6.5 (5.0 - 7.8) 18.7 (10.8 - 28.2) 76 66 10.7 (8.2 - 12.2) 39.5 (28.5-50.2) is so 11.7 (7.1 - 17.0) 50.7 (38.9 - 61.3) Patent Application Publication Mar. 22, 2012 Sheet 14 of 15 US 2012/0070404 A1 - £84,?edN8 1814&N8ON-- ÞI*31.I o rt se Ayqeqold jealAuns Patent Application Publication Mar. 22, 2012 Sheet 15 of 15 US 2012/0070404 A1 Fig. 15 Grade 3 and 4 Treatment Related Adverse Events by Arm V Arm Grade 3 Grade 4 n (%) n (%) Dehydration NOTAVOCEPT 12 (16) 1 (1) TAVOCEPT 6 (8) 1 (1) NOTAVOCEPT 13 (17) aSCa TAVOCEPT 8 (10) NOTAVOCEPT 7 (9) O Vikk TAVOCEPT 2 (3) O NOTAVOCEPT 9 (12) TAVOCEPT O US 2012/0070404 A1 Mar. 22, 2012 INCREASING CANCER PATIENT SURVIVAL cancer, endometrial cancer, Vaginal cancer, prostate cancer, TIME BY ADMINISTRATION OF uterine cancer, hepatic cancer, pancreatic cancer, and adeno DTHO-CONTAINING COMPOUNDS carcinoma. 0004. Thioredoxin and glutaredoxin are members of the thioredoxin Superfamily; that mediate disulfide exchange via 0001. The present invention relates to novel pharmaceuti their Cys-containing catalytic sites. While glutaredoxins cal compositions, methods, and kits used for the treatment of mostly reduce mixed disulfides containing glutathione, cancer and other medical conditions. More specifically, the thioredoxins are involved in the maintenance of protein sulf present invention relates to novel pharmaceutical composi hydryls in their reduced state via disulfide bond reduction. tions, methods, and kits comprising medicaments used for the See, e.g., Print, W. A., et al., The role of the thioredoxin and treatment of lung cancer, adenocarcinoma, and other medical glutaredoxin pathways in reducing protein disulfide bonds in conditions. In addition, the present invention also relates to the Escherichia coli cytoplasm. J. Biol. Chem. 272:15661 compositions, methods of treatment, and kits which cause an 15667 (1996). The reduced form of thioredoxin is generated increase in time of Survival in cancer patients, wherein the by the action of thioredoxin reductase; whereas glutathione cancer either: (i) overexpresses thioredoxin or glutaredoxin provides directly the reducing potential for regeneration of and/or (ii) exhibits evidence of thioredoxin- or glutaredoxin the reduced form of glutaredoxin. Glutaredoxins are oxidized mediated resistance to one or more chemotherapeutic inter by Substrates, and reduced non-enzymatically by glutathione. ventions. The present invention also relates to methods and In contrast to thioredoxins, which are reduced by thioredoxin kits for the administration of said compositions to properly reductase, no oxidoreductase or Substrate, other than those treat cancer patients. Additionally, the present invention described in the present invention, has been reported to spe relates to methods and kits for quantitatively determining the cifically reduce glutaredoxins.
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