US2018117110A1PendingUtilityA1

Method of treating cancer

42
Assignee: WALTER & ELIZA HALL INST MEDICAL RESPriority: Oct 3, 2014Filed: Oct 3, 2014Published: May 3, 2018
Est. expiryOct 3, 2034(~8.2 yrs left)· nominal 20-yr term from priority
Inventors:Najoua LalaouiJohn SilkeDavid Vaux
A61P 35/00A61K 38/005A61K 45/06C12N 9/1205C12Y 207/11024A61K 38/04A61K 38/191C07K 5/06026A61K 31/7125A61K 38/05
42
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Claims

Abstract

The present invention provides a method of treating cancer in a subject wherein the method comprising administering to the subject an IAP antagonist and a p38 and/or a MK2 inhibitor.

Claims

exact text as granted — not AI-modified
1 . A method of treating cancer in a subject, the method comprising administering to the subject an IAP antagonist and a p38 inhibitor or a MK2 inhibitor, or both a p38 inhibitor and a MK2 inhibitor. 
     
     
         2 . The method as claimed in  claim 1  wherein the IAP antagonist is administered with a p38 antagonist or a MK2 inhibitor. 
     
     
         3 . The method as claimed in  claim 1  wherein the IAP is one or more of cIAP1, cIAP2 and XIAP. 
     
     
         4 . The method as claimed in  claim 1  wherein the antagonist is a SMAC mimetic. 
     
     
         5 . The method as claimed in  claim 4 , wherein the SMAC mimetic comprises one or more of the following characteristics:
 (a) the SMAC mimetic is bivalent;   (b) the SMAC mimetic derepresses XIAP-mediated caspase-3 repression;   (c) the SMAC mimetic degrades cIAP-1 not bound to TRAF2 as well as cIAP1 bound to TRAF2;   (d) the SMAC mimetic degrades cIAP-2 bound to TRAF2 but does not degrade cIAP-2 not bound to TRAF2;   (e) the SMAC mimetic weakly degrades cIAP-2 not bound to TRAF2 relative to degradation of cIAP-2 bound to TRAF; and   (f) the SMAC mimetic has the general structure [P1-P2-P3-P4] or [P1-P2-P3-P4]-L-[P1′-P2′-P3′-P4′], wherein P1-P2-P3- and P1′-P2′-P3′- correspond to peptide replacements or peptidomimetics of the N-terminal Ala-Val-Pro-tripeptide of mature SMAC and P4 and P4′ correspond to amino acid replacements of Phe, Tyr, Ile, or Val, and L is a linking group, or bond, covalently linking [P1-P2-P3-P4] to [P1′-P2′-P3′-P4′].   
     
     
         6 . The method as claimed in  claim 4  wherein the SMAC mimetic is birinapant, GT13072 or GT12911. 
     
     
         7 . The method as claimed in  claim 1  wherein the antagonist reduces expression of the IAP gene. 
     
     
         8 . The method as claimed in  claim 7  wherein the IAP gene is the cIAP1, cIAP2 or XIAP gene. 
     
     
         9 . The method as claimed in  claim 7  wherein the antagonist is siRNA, shRNA or miRNA. 
     
     
         10 . The method as claimed in  claim 9  wherein the siRNA, shRNA or miRNA is targeted against a sequence selected from the group consisting of NCBI Reference Sequence: NM_001166.4, NCBI Reference Sequence: NM_001256163.1, NCBI Reference Sequence: NM_001256166.1, GenBank: DQ068066.1, NCBI Reference Sequence: NM_001165.4, NCBI Reference Sequence: NM_182962.2, GenBank: BC037420.1, NCBI Reference Sequence: NM_001167.3, NCBI Reference Sequence: NM_001204401.1, NCBI Reference Sequence: NR_037916.1, NCBI Reference Sequence: NG_007264.1, NCBI reference sequence NM_001167.3, NCBI reference sequence NM_001204401.1 and NCBI reference sequence NR_037916.1. 
     
     
         11 . The method as claimed in  claim 1  wherein the IAP antagonist is administered in combination with a p38 inhibitor. 
     
     
         12 . The method as claimed in  claim 11  wherein the p38 inhibitor is selected from the group consisting of LY222820, SCIO-469, BIRB 796, VX-702, SB 239063, SB202190, BMS 582949, SB203580, GW856553X, Skepinone-L, PH-797804, VX-745, TAK-715, JX-401, CAY10571, SB220025, AMG 548, ML 3403, SKF 86002, SX 011, SB-681323, SB 242235, CMPD-1, DBM 1285 dihydrochloride, EO 1428 and RWJ 67657. 
     
     
         13 . The method as claimed in  claim 11  wherein the p38 inhibitor reduces expression of the p38 gene. 
     
     
         14 . The method as claimed in  claim 13  wherein the p38 inhibitor is siRNA, shRNA or miRNA. 
     
     
         15 . The method as claimed in  claim 14  wherein the siRNA, shRNA or miRNA is targeted against the sequence of p38α (MAPK14) Accession NM_001315 or p38β (MAPK11) Accession NM_002751. 
     
     
         16 . The method as claimed in in  claim 1  wherein the IAP antagonist is administered in combination with a MK2 inhibitor. 
     
     
         17 . The method as claimed in  claim 16  wherein the MK2 inhibitor is selected from the group consisting of PF-3644022, PHA 767491, MK-2 Inhibitor III and MK-2 Inhibitor IV. 
     
     
         18 . The method as claimed in  claim 16  wherein the MK2 inhibitor reduces expression of the MK2 gene. 
     
     
         19 . The method as claimed in  claim 18  wherein the MK2 inhibitor is siRNA, shRNA or miRNA. 
     
     
         20 . The method as claimed in  claim 19  wherein the siRNA, shRNA or miRNA is targeted against the sequence of MK2 (MAPKAPK2) Accession NM_004759. 
     
     
         21 . The method as claimed in  claim 1  wherein the method comprises administering a polynucleotide encoding the IAP antagonist. 
     
     
         22 . The method as claimed in in  claim 1  wherein the cancer is selected from AML, myelodysplastic syndrome, multiple myeloma, ALL, breast cancer, colorectal cancer and ovarian cancer. 
     
     
         23 . A pharmaceutical preparation comprising an IAP antagonist and a p38 or a MK2 inhibitor, or both a p38 and MK2 inhibitor. 
     
     
         24 . The pharmaceutical preparation as claimed in  claim 23  comprising an IAP antagonist and a p38 or a MK2 inhibitor. 
     
     
         25 . The preparation as claimed in  claim 23  wherein the IAP is one or more of cIAP1, cIAP2 and XIAP or a combination thereof. 
     
     
         26 . The preparation as claimed in  claim 23  wherein the antagonist is a SMAC mimetic. 
     
     
         27 . The preparation as claimed in  claim 26 , wherein the SMAC mimetic comprises one or more of the following characteristics:
 (a) the SMAC mimetic is bivalent;   (b) the SMAC mimetic derepresses XIAP-mediated caspase-3 repression;   (c) the SMAC mimetic degrades cIAP-1 not bound to TRAF2 as well as cIAP1 bound to TRAF2;   (d) the SMAC mimetic degrades cIAP-2 bound to TRAF2 but does not degrade cIAP-2 not bound to TRAF2;   (e) the SMAC mimetic weakly degrades cIAP-2 not bound to TRAF2 relative to degradation of cIAP-2 bound to TRAF; and   (f) the SMAC mimetic has the general structure [P1-P2-P3-P4] or [P1-P2-P3-P4]-L-[P1′-P2′-P3′-P4′], wherein P1-P2-P3- and P1′-P2′-P3′- correspond to peptide replacements or peptidomimetics of the N-terminal Ala-Val-Pro-tripeptide of mature SMAC and P4 and P4′ correspond to amino acid replacements of Phe, Tyr, Ile, or Val, and L is a linking group, or bond, covalently linking [P1-P2-P3-P4] to [P1′-P2′-P3′-P4′].   
     
     
         28 . The preparation as claimed in  claim 26  wherein the SMAC mimetic is birinapant, GT13072 or GT12911. 
     
     
         29 . The preparation as claimed in  claim 26  wherein the antagonist reduces expression of the IAP gene. 
     
     
         30 . The preparation as claimed in  claim 29  wherein the IAP gene is the cIAP1, cIAP2 or XIAP gene. 
     
     
         31 . The preparation as claimed in  claim 29  wherein the antagonist is siRNA, shRNA or miRNA. 
     
     
         32 . The preparation as claimed in  claim 31  wherein the siRNA, shRNA or miRNA is targeted against a sequence selected from the group consisting of NCBI Reference Sequence: NM_001166.4, NCBI Reference Sequence: NM_001256163.1, NCBI Reference Sequence: NM_001256166.1, GenBank: DQ068066.1, NCBI Reference Sequence: NM_001165.4, NCBI Reference Sequence: NM_182962.2, GenBank: BC037420.1, NCBI Reference Sequence: NM_001167.3, NCBI Reference Sequence: NM_001204401.1, NCBI Reference Sequence: NR_037916.1, NCBI Reference Sequence: NG_007264.1, NCBI reference sequence NM_001167.3, NCBI reference sequence NM_001204401.1 and NCBI reference sequence NR_037916.1. 
     
     
         33 . The preparation as claimed in  claim 23  wherein the preparation comprises an IAP antagonist and a p38 inhibitor. 
     
     
         34 . The preparation as claimed in  claim 33  wherein the p38 inhibitor is selected from the group consisting of LY222820, SCIO-469, BIRB 796, VX-702, SB 239063, SB202190, BMS 582949, SB203580, GW856553X, Skepinone-L, PH-797804, VX-745, TAK-715, JX-401, CAY10571, SB220025, AMG 548, ML 3403, SKF 86002, SX 011, SB-681323, SB 242235, CMPD-1, DBM 1285 dihydrochloride, EO 1428 and RWJ 67657. 
     
     
         35 . The preparation as claimed in  claim 33  wherein the p38 inhibitor reduces expression of the p38 gene. 
     
     
         36 . The preparation as claimed in  claim 35  wherein the p38 inhibitor is siRNA, shRNA or miRNA. 
     
     
         37 . The preparation as claimed in  claim 36  wherein the siRNA, shRNA or miRNA is targeted against the sequence of p38α (MAPK14) Accession NM_001315 or p38β (MAPK11) Accession NM_002751. 
     
     
         38 . The preparation as claimed in  claim 23  wherein the preparation comprises an IAP antagonist and a MK2 inhibitor. 
     
     
         39 . The preparation as claimed in  claim 38  wherein the MK2 inhibitor is selected from the group consisting of PF-3644022, PHA 767491, MK-2 Inhibitor III and MK-2 Inhibitor IV. 
     
     
         40 . The preparation as claimed in  claim 38  wherein the MK2 inhibitor reduces expression of the MK2 gene. 
     
     
         41 . The preparation as claimed in  claim 40  wherein the MK2 inhibitor is siRNA, shRNA or miRNA. 
     
     
         42 . The preparation as claimed in  claim 41  wherein the siRNA, shRNA or miRNA is targeted against the sequence of MK2 (MAPKAPK2) Accession NM_004759.

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