Combination of an inhibitor of parp with an inhibitor of gsk-3 or dot1l

Abstract

Provided herein is a pharmaceutical combination comprising (a) a poly-(ADP-ribose)-polymerase (PARP) inhibitor and (b) a second agent comprising (i) an inhibitor of glycogen synthase kinase 3 (GSK-3) or (ii) an inhibitor of disrupter of telomeric silencing 1-like (DOT1L). Also provided is a method of treating a subject suffering from acute myeloid leukaemia, comprising administering to the subject a therapeutically effective amount of the pharmaceutical combination. There is also described herein a method for selecting a therapy for a subject suffering from acute myeloid leukaemia, comprising determining whether a chromosomal abnormality at 11q23 is present in a sample obtained from the subject; wherein if the chromosomal abnormality at 11q23 is present in the sample, a therapy comprising combined administration of (a) a poly-(ADP-ribose)-polymerase (PARP) inhibitor and (b) a second agent comprising (i) an inhibitor of glycogen synthase kinase 3 (GSK-3) or (ii) an inhibitor of disrupter of telomeric silencing 1-like (DOT1L)is selected for the subject.

1 . A pharmaceutical combination comprising:
 (a) a poly-(ADP-ribose)-polymerase (PARP) inhibitor; and   (b) a second agent comprising:
 (i) an inhibitor of glycogen synthase kinase 3 (GSK-3); or 
 (ii) an inhibitor of disrupter of telomeric silencing 1-like (DOT1L); or 
 (iii) an inhibitor of menin. 
   
     
     
         2 . A pharmaceutical combination according to  claim 1 , wherein the second agent is an inhibitor of glycogen synthase kinase 3 (GSK-3). 
     
     
         3 . A pharmaceutical combination according to  claim 2 , wherein the GSK-3 inhibitor comprises lithium or a pharmaceutically acceptable salt thereof, SB216763, SB415286, 6-bromo-indirubin-3′-oxime (6-BIO), hymenialdisine, dibromocantharelline, CT98014, CT98023, CT99021, TWS119, AR-A014418, AZD-1080, kenpaullone, alsterpaullone, cazpaullone, aloisine A, manzamine A, palinurine, tricantine, TDZD-8, NP00111, NP031115, NP03112, HMK-32 or L803-mts. 
     
     
         4 . A pharmaceutical combination according to  claim 1 , wherein the second agent is an inhibitor of disrupter of telomeric silencing 1-like (DOT1L). 
     
     
         5 . A pharmaceutical combination according to  claim 4 , wherein the inhibitor of DOT1L is EPZ-5676 or EPZ4777. 
     
     
         6 . A pharmaceutical combination according to  claim 1 , wherein the PARP inhibitor is selected from olaparib, veliparib, CEP-8983, rucaparib, E7016, BMN-673, INO-1001, CEP-9722, iniparib, or K4827, analogues thereof, and derivatives thereof. 
     
     
         7 - 24 . (canceled) 
     
     
         25 . A pharmaceutical combination according to  claim 3 , wherein the lithium salt comprises lithium carbonate, citrate, chloride, orotate, bromide or chloride. 
     
     
         26 . A pharmaceutical combination according to  claim 1 , wherein the second agent is an inhibitor of menin. 
     
     
         27 . A pharmaceutical combination according to  claim 26 , wherein the inhibitor of menin comprises MI 463, MI 503, or MI 136. 
     
     
         28 . A method of treatment of mixed lineage leukemia (MLL) subtype of acute myeloid leukemia (AML) in a subject in need thereof, the method comprising administering to the subject a combination, in synergistically effective amounts, of:
 (a) a poly-(ADP-ribose)-polymerase (PARP) inhibitor, wherein the PARP inhibitor is selected from olaparib, veliparib, CEP-8983, rucaparib, E7016, BMN-673, INO-1001, CEP-9722, iniparib, or K4827, or analogues or derivatives thereof; and   (b) a second agent comprising:
 (i) an inhibitor of glycogen synthase 3 (GSK-3), wherein the GSK-3 inhibitor comprises lithium or a salt thereof, SB216763, SB415286, 6-bromo-indirubin-3′-oxime (6-BIO), hymenialdisine, dibromocantharelline, CT98014, CT98023, CT99021, TWS119, AR-A014418, AZD-1080, kenpaullone, alsterpaullone, cazpaullone, aloisine A, manzamine A, palinurine, tricantine, TDZD-8, NP00111, NP031115, NP03112, HMK-32 or L803-mts; or 
 (ii) an inhibitor of telomeric silencing 1-like (DOT1L), wherein the inhibitor of DOT1L comprises EPZ-5676 or EPZ-4777; or 
 (iii) an inhibitor of menin, wherein the inhibitor of menin comprises MI 463, MI 503, or MI 136; 
   wherein the subject has a cytogenic abnormality at chromosome 11q23 resulting in a rearrange MLL gene and/or expression of a MLL fusion protein.   
     
     
         29 . A method of treatment according to  claim 28 , wherein the combination comprises:
 (a) a poly-(ADP-ribose)-polymerase (PARP) inhibitor, wherein the PARP inhibitor is selected from olaparib, veliparib, CEP-8983, rucaparib, E7016, BMN-673 or INO-1001, or analogues or derivatives thereof; and   (b) a second agent comprising
 (i) an inhibitor of glycogen synthase 3 (GSK-3), wherein the GSK-3 inhibitor comprises hymenialdisine, dibromocantharelline, CT98014, CT98023, CT99021, TWS119, AR-A014418, AZD-1080, kenpaullone, alsterpaullone, cazpaullone, aloisine A, manzamine A, palinurine, tricantine, TDZD-8, NP00111, NP031115, NP03112, HMK-32 or L803-mts; or 
 (iii) an inhibitor of menin, wherein the inhibitor of menin comprises MI 463, MI 503, or MI 136. 
   
     
     
         30 . A method of treatment according to  claim 28 , wherein the combination comprises:
 (a) a poly-(ADP-ribose)-polymerase (PARP) inhibitor, wherein the PARP inhibitor is selected from CEP-9722, iniparib, or K4827, or analogues or derivatives thereof; and   (b) a second agent comprising
 (i) an inhibitor of glycogen synthase 3 (GSK-3), wherein the GSK-3 inhibitor comprises lithium or a salt thereof, SB216763, SB415286, 6-bromo-indirubin-3′-oxime (6-BIO), hymenialdisine, dibromocantharelline, CT98014, CT98023, CT99021, TWS119, AR-A014418, AZD-1080, kenpaullone, alsterpaullone, cazpaullone, aloisine A, manzamine A, palinurine, tricantine, TDZD-8, NP00111, NP031115, NP03112, HMK-32 or L803-mts; or 
 (ii) an inhibitor of telomeric silencing 1-like (DOT1L), wherein the inhibitor of DOT1L comprises EPZ-5676 or EPZ-4777; or 
 (iii) an inhibitor of menin, wherein the inhibitor of menin comprises MI 463, MI 503, or MI 136. 
   
     
     
         31 . A method according to  claim 28 , wherein the second agent is an inhibitor of glycogen synthase kinase 3 (GSK-3). 
     
     
         32 . A method according to  claim 31 , wherein the GSK-3 inhibitor comprises lithium or a pharmaceutically acceptable salt thereof, SB216763, SB415286, 6-bromo-indirubin-3′-oxime (6-BIO), hymenialdisine, dibromocantharelline, CT98014, CT98023, CT99021, TWS119, AR-A014418, AZD-1080, kenpaullone, alsterpaullone, cazpaullone, aloisine A, manzamine A, palinurine, tricantine, TDZD-8, NP00111, NP031115, NP03112, HMK-32 or L803-mts. 
     
     
         33 . A method according to  claim 32 , wherein the lithium salt comprises lithium carbonate, lithium citrate, lithium chloride, lithium orotate, lithium bromide or lithium chloride. 
     
     
         34 . A method according to  claim 28 , wherein the second agent is an inhibitor of disrupter of telomeric silencing 1-like (DOT1L). 
     
     
         35 . A method according to  claim 34 , wherein the inhibitor of DOT1L is EPZ-5676 or EPZ-4777. 
     
     
         36 . A method for treatment of a subject suffering from mixed lineage leukaemia (MLL) subtype of acute myeloid leukaemia, comprising:
 identifying a chromosomal abnormality at 11q23 in the subject; and   administering to the subject identified as having the chromosomal abnormality at 11q23 a therapy comprising combined administration, in synergistic amounts, of (a) a poly-(ADP-ribose)-polymerase (PARP) inhibitor, wherein the PARP inhibitor is selected from olaparib, veliparib, CEP-8983, rucaparib, E7016, BMN-673, INO-1001, iniparib, CEP-9722, or K4827, or analogues or derivatives thereof; and   (b) a second agent comprising
 (i) an inhibitor of glycogen synthase kinase 3 (GSK-3), wherein the GSK-3 inhibitor comprises lithium or a salt thereof, SB216763, SB415286, 6-bromo-indirubin-3′-oxime (6-BIO), hymenialdisine, dibromocantharelline, CT98014, CT98023, CT99021, TWS119, AR-A014418, AZD-1080, kenpaullone, alsterpaullone, cazpaullone, aloisine A, manzamine A, palinurine, tricantine, TDZD-8, NP00111, NP031115, NP03112, HMK-32 or L803-mts; or 
 (ii) an inhibitor of disrupter of telomeric silencing 1-like (DOT1L), wherein the inhibitor of DOT1L comprises EPZ-5676 or EPZ-4777; or 
 (iii) an inhibitor of menin, wherein the inhibitor of menin comprises MI 463, MI 503, or MI 136. 
   
     
     
         37 . A pharmaceutical composition comprising a PARP inhibitor and a second agent as defined in  claim 1 . 
     
     
         38 . A kit comprising a PARP inhibitor and a second agent as defined in  claim 1 . 
     
     
         39 . A method of treatment of mixed lineage leukemia (MLL) subtype of acute myeloid leukemia (AML) in a subject in need thereof, the method comprising administering to the subject a PARP inhibitor and second agent as defined in  claim 1 , in synergistically effective amounts.