Prognostic biomarkers for TTK inhibitor chemotherapy
A method for identifying a tumor that is susceptible to treatment with a TTK inhibitor, including: a) providing a sample of a tumor; b) determining the presence of a mutated CTNNB1 gene in the sample, wherein the mutation is located in exon 3 of CTNNB1 and the presence of a mutated CTNNB1 gene indicates the tumor is susceptible to treatment with a TTK inhibitor. Alternatively, step b) is replaced by the step of determining the presence of a mutated CTNNB1 protein in the sample, wherein the mutation is located in exon 3 of CTNNB1 and the presence of a mutated CTNNB1 protein indicates the tumor is susceptible to treatment with a TTK inhibitor. In a further alternative, step b) includes determining an altered expression of a CTNNB1 regulated gene, whereby an altered expression of a CTNNB1 regulated gene indicates the tumor is susceptible to treatment with a TTK inhibitor.
1. A method for treating a tumor in a human individual or an animal that is susceptible to treatment with a TTK inhibitor, the method comprising:
determining that the tumor is susceptible to treatment with the TTK inhibitor when the presence of a mutated CTNNB1-encoded protein, the corresponding CTNNB1 gene having a mutation located in exon 3, has been detected in a tumor sample from the human individual or animal; and
treating, with the TTK inhibitor, the human individual or animal whose tumor is determined to be susceptible to treatment with the TTK inhibitor,
wherein the TTK inhibitor is a chemical compound belonging to the class of compounds according to Formula I:
wherein:
R 1 is selected from the group consisting of:
R 11 is H, halogen, (1-2C)alkyl, (2-3C)alkenyl, (2-3C)alkynyl or (1-2C)alkoxy, all alkyl and alkoxy groups optionally being substituted with one or more halogen;
R 12 is H, halogen, (1-2C)alkyl or (1-2C)alkoxy;
R 13 is R 131 CH 2 , R 132 O, R 133 R 134 N, R 135 C(O) R 136 S, R 136 S(O), R 136 S(O)(NH), R 137 SO 2 , (2-7C)heterocycloalkyl, or (1-5C)heteroaryl each heterocycloalkyl or heteroaryl optionally being substituted with (1-2C)alkyl, fluoro, hydroxyl, oxo, (1-2C)alkoxy, (1-6C)alkylcarbonyl, (1-6C)alkylsulfonyl, (1-5C)alkoxycarbonyl, (1-6C)alkylaminocarbonyl, (3-6C)cycloalkylcarbonyl, (2-7C)heterocycloalkylcarbonyl or di[(1-2C)alkyl]amino, each alkylcarbonyl, alkylsulfonyl, alkoxycarbonyl, alkylaminocarbonyl, cycloalkylcarbonyl or heterocycloalkylcarbonyl optionally being substituted with (1-2C)alkyl, fluoro, hydroxyl, cyano, oxo or (1-2C)alkoxy;
R 131 is (1-6C)alkylcarbonylamino, (3-6C)cycloalkylcarbonylamino or (2-7C)heterocycloalkylcarbonylamino each optionally substituted with one or more groups selected from (1-2C)alkyl, fluoro, hydroxyl or (1-2C)alkoxy;
R 132 is (1-6C)alkyl, (3-6C)cycloalkyl, (2-7C)heterocycloalkyl, (6-10C)aryl or (1-5C)heteroraryl each optionally substituted with one or more groups selected from (1-2C)alkyl, halogen, hydroxyl, (1-2C)alkoxy, di[(1-2C)alkyl]amino or (2-7C)heterocycloalkyl;
R 133 is (1-6C)alkyl, (3-6C)cycloalkyl, (2-7C)heterocycloalkyl (1-6C)alkylcarbonyl, (1-5C)alkoxycarbonyl, (3-6C)cycloalkylcarbonyl or (2-7C)heterocycloalkylcarbonyl, each optionally substituted with one or more groups selected from (1-2C)alkyl, halogen, hydroxyl or (1-2C)alkoxy, di[(1-2C)alkyl]amino or (2-7C)heterocycloalkyl;
R 134 is hydrogen or (1-2C)alkyl;
R 135 is (2-7C)heterocycloalkyl, (1-6C)alkylamino, di[(1-6C)alkyl]amino, (2-7C)heterocycloalkylamino or (3-6C)cycloalkylamino each optionally substituted with one or more groups selected from (1-2C)alkyl, fluoro, hydroxyl, (1-2C)alkoxy, di[(1-2C)alkyl]amino, (2-7C)heterocycloalkyl, oxo, cyano or amino;
R 136 is (1-6C)alkyl, (3-6C)cycloalkyl, (2-7C)heterocycloalkyl each optionally substituted with one or more groups selected from (1-2C)alkyl, fluoro, hydroxyl or (1-2C)alkoxy;
R 137 is (1-6C)alkyl, (3-6C)cycloalkyl, (2-7C)heterocycloalkyl, (1-6C)alkylamino, di[(1-6C)alkyl]amino, (2-7C)heterocycloalkylamino or (3-6C)cycloalkylamino, each optionally substituted with one or more groups selected from (1-2C)alkyl, fluoro, hydroxyl or (1-2C)alkoxy;
R 14 is H, halogen, (1-2C)alkyl or (1-2C)alkoxy; and
R 15 is H, halogen;
in the above Formula I, R 2 is selected from the group consisting of:
R 21 is H, halogen, (1-3C)alkyl, (1-2C)alkoxy, hydroxy(1-2C)alkyl, (3-4C)cycloalkyl, (2-3C)alkenyl or cyano;
R 22 is H, halogen, (1-2C)alkyl or (1-2C)alkoxy;
R 23 is H, halogen, (1-2C)alkyl, (1-2C)alkoxy, cyano or hydroxy;
R 24 is H, halogen, (1-2C)alkyl or (1-2C)alkoxy;
R 25 is H, halogen, (1-3C)alkyl, (1-2C)alkoxy, hydroxy(1-2C)alkyl, (3-4C)cycloalkyl, (2-3C)alkenyl or cyano;
R 26 is H, (1-6C)alkyl, (3-6C)cycloalkyl, (2-5C)heterocycloalkyl, (1-2C)alkoxy[(2-4C)alkoxy], (1-6C)alkyl, wherein n represents an integer of 1, 2, 3 or 4, all alkyl, heterocycloalkyl and (1-2C)alkoxy[(2-4C)alkoxy](1-6C)alkyl groups optionally substituted with one or more groups selected from (1-2C)alkyl, (1-2C)alkoxy, hydroxyl, oxo, amino, (3-6C)cycloalkyl, di[(1-2C)alkyl]amino or (2-5C)heterocycloalkyl; and wherein
in the above Formula I only one of R 21 and R 25 in R 2 can be H.
2. The method according to claim 1 , wherein said mutation results in a substitution of one or more serine or threonine residues in the corresponding CTNNB1-encoded protein, or wherein said mutation is a deletion of one or more serine or threonine residues in the corresponding CTNNB1-encoded protein.
3. The method according to claim 2 , wherein said mutation results in a substitution of one or more serine or threonine residues in the corresponding CTNNB1-encoded protein at a position selected from S33, S37, S45 and T41, or wherein said mutation is a deletion of one or more serine or threonine residues in the corresponding CTNNB1-encoded protein at a position selected from S33, S37, S45 and T41.
4. The method according to claim 1 , wherein the mutation results in a substitution or a deletion of the serine residue corresponding to codon 33 of CTNNB1.
5. The method according to claim 1 , wherein the mutation results in a substitution or a deletion of the threonine residue corresponding to codon 41 of CTNNB1.
6. The method according to claim 1 , wherein the mutation results in a substitution or a deletion of the serine residue corresponding to codon 45 of CTNNB1.
7. The method according to claim 1 , wherein the mutation results in a substitution or a deletion of the serine residue corresponding to codon 37 of CTNNB1.
8. The method according to claim 1 , wherein the presence of the mutated CTNNB1-encoded protein has been detected by detecting a mutated CTNNB1 gene having a mutation located in exon 3 in tumor DNA in the tumor sample.
9. The method according to claim 8 , wherein the tumor DNA is taken from a tumor biopsy.
10. The method according to claim 8 , wherein the tumor DNA is derived from circulating tumor DNA.
11. The method according to claim 1 , wherein the presence of the mutated CTNNB1-encoded protein, having a mutation in exon 3, has been detected by sequencing tumor mRNA in the tumor sample.
12. The method according to claim 1 , wherein the presence of the mutated CTNNB1-encoded protein has been detected by analyzing the amino acid sequence or phosphorylation of β-catenin in the tumor sample.
13. The method according to claim 1 , wherein the tumor sample is taken from a tumor biopsy.
14. The method according to claim 1 , wherein the tumor sample is taken from circulating tumor cells.
15. A method for treating a tumor in a human individual or an animal, the method comprising:
detecting whether a mutated CTNNB1-encoded protein, the corresponding CTNNB1 gene having a mutation located in exon 3, is present in a tumor sample from the human individual or animal;
diagnosing the human individual or animal as being susceptible to treatment with a TTK inhibitor when the presence of the mutated CTNNB1-encoded protein in the tumor sample is detected; and
treating the diagnosed human individual or animal with the TTK inhibitor,
wherein the TTK inhibitor is a chemical compound belonging to the class of compounds according to Formula I:
wherein:
R 1 is selected from the group consisting of:
R 11 is H, halogen, (1-2C)alkyl, (2-3C)alkenyl, (2-3C)alkynyl, or (1-2C)alkoxy, all alkyl and alkoxy groups optionally being substituted with one or more halogen;
R 12 is H, halogen, (1-2C)alkyl or (1-2C)alkoxy;
R 13 is R 131 CH 2 , R 132 O, R 133 R 134 N, R 136 C(O) R 136 S, R 136 S(O), R 136 S(O)(NH), R 137 SO 2 , (2-7C)heterocycloalkyl, or (1-5C)heteroaryl each heterocycloalkyl or heteroaryl optionally being substituted with (1-2C)alkyl, fluoro, hydroxyl, oxo, (1-2C)alkoxy, (1-6C)alkylcarbonyl, (1-6C)alkylsulfonyl, (1-5C)alkoxycarbonyl, (1-6C)alkylaminocarbonyl, (3-6C)cycloalkylcarbonyl, (2-7C)heterocycloalkylcarbonyl or di[(1-2C)alkyl]amino, each alkylcarbonyl, alkylsulfonyl, alkoxycarbonyl, alkylaminocarbonyl, cycloalkylcarbonyl or heterocycloalkylcarbonyl optionally being substituted with (1-2C)alkyl, fluoro, hydroxyl, cyano, oxo or (1-2C)alkoxy;
R 131 is (1-6C)alkylcarbonylamino, (3-6C)cycloalkylcarbonylamino or (2-7C)heterocycloalkylcarbonylamino each optionally substituted with one or more groups selected from (1-2C)alkyl, fluoro, hydroxyl or (1-2C)alkoxy;
R 132 is (1-6C)alkyl, (3-6C)cycloalkyl, (2-7C)heterocycloalkyl, (6-10C)aryl or (1-5C)heteroraryl each optionally substituted with one or more groups selected from (1-2C)alkyl, halogen, hydroxyl, (1-2C)alkoxy, di[(1-2C)alkyl]amino or (2-7C)heterocycloalkyl;
R 133 is (1-6C)alkyl, (3-6C)cycloalkyl, (2-7C)heterocycloalkyl (1-6C)alkylcarbonyl, (1-5C)alkoxycarbonyl, (3-6C)cycloalkylcarbonyl or (2-7C)heterocycloalkylcarbonyl, each optionally substituted with one or more groups selected from (1-2C)alkyl, halogen, hydroxyl or (1-2C)alkoxy, di[(1-2C)alkyl]amino or (2-7C)heterocycloalkyl;
R 134 is hydrogen or (1-2C)alkyl;
R 135 is (2-7C)heterocycloalkyl, (1-6C)alkylamino, di[(1-6C)alkyl]amino, (2-7C)heterocycloalkylamino or (3-6C)cycloalkylamino each optionally substituted with one or more groups selected from (1-2C)alkyl, fluoro, hydroxyl, (1-2C)alkoxy, di[(1-2C)alkyl]amino, (2-7C)heterocycloalkyl, oxo, cyano or amino;
R 136 is (1-6C)alkyl, (3-6C)cycloalkyl, (2-7C)heterocycloalkyl each optionally substituted with one or more groups selected from (1-2C)alkyl, fluoro, hydroxyl or (1-2C)alkoxy;
R 137 is (1-6C)alkyl, (3-6C)cycloalkyl, (2-7C)heterocycloalkyl, (1-6C)alkylamino, di[(1-6C)alkyl]amino, (2-7C)heterocycloalkylamino or (3-6C)cycloalkylamino, each optionally substituted with one or more groups selected from (1-2C)alkyl, fluoro, hydroxyl or (1-2C)alkoxy;
R 14 is H, halogen, (1-2C)alkyl or (1-2C)alkoxy; and
R 15 is H, halogen;
in the above Formula I, R 2 is selected from the group consisting of:
R 21 is H, halogen, (1-3C)alkyl, (1-2C)alkoxy, hydroxy(1-2C)alkyl, (3-4C)cycloalkyl, (2-3C)alkenyl or cyano;
R 22 is H, halogen, (1-2C)alkyl or (1-2C)alkoxy;
R 23 is H, halogen, (1-2C)alkyl, (1-2C)alkoxy, cyano or hydroxy;
R 24 is H, halogen, (1-2C)alkyl or (1-2C)alkoxy;
R 25 is H, halogen, (1-3C)alkyl, (1-2C)alkoxy, hydroxy(1-2C)alkyl, (3-4C)cycloalkyl, (2-3C)alkenyl or cyano;
R 26 is H, (1-6C)alkyl, (3-6C)cycloalkyl, (2-5C)heterocycloalkyl, (1-2C)alkoxy[(2-4C)alkoxy], (1-6C)alkyl, wherein n represents an integer of 1, 2, 3 or 4, all alkyl, heterocycloalkyl and (1-2C)alkoxy[(2-4C)alkoxy](1-6C)alkyl groups optionally substituted with one or more groups selected from (1-2C)alkyl, (1-2C)alkoxy, hydroxyl, oxo, amino, (3-6C)cycloalkyl, di[(1-2C)alkyl]amino or (2-5C)heterocycloalkyl; and wherein
in the above Formula I only one of R 21 and R 25 in R 2 can be H.
16. The method according to claim 1 , wherein in Formula I:
R 1 is
R 11 is H, halogen, (1-2C)alkyl, (2-3C)alkenyl, (2-3C)alkynyl, or (1-2C)alkoxy, all alkyl and alkoxy groups optionally being substituted with one or more halogen;
R 12 is H, halogen, (1-2C)alkyl or (1-2C)alkoxy;
R 13 is R 132 O, R 135 C(O), (2-7C)heterocycloalkyl, or (1-5C)heteroaryl each heterocycloalkyl or heteroaryl optionally being substituted with (1-2C)alkyl, fluoro, hydroxyl, oxo, (1-2C)alkoxy, (1-6C)alkylcarbonyl, (1-6C)alkylsulfonyl, (1-5C)alkoxycarbonyl, (1-6C)alkylaminocarbonyl, (3-6C)cycloalkylcarbonyl, (2-7C)heterocycloalkylcarbonyl or di[(1-2C)alkyl]amino, each alkylcarbonyl, alkylsulfonyl, alkoxycarbonyl, alkylaminocarbonyl, cycloalkylcarbonyl or heterocycloalkylcarbonyl optionally being substituted with (1-2C)alkyl, fluoro, hydroxyl, cyano, oxo or (1-2C)alkoxy;
R 132 is (1-6C)alkyl, (3-6C)cycloalkyl, (2-7C)heterocycloalkyl, (6-10C)aryl or (1-5C)heteroraryl each optionally substituted with one or more groups selected from (1-2C)alkyl, halogen, hydroxyl, (1-2C)alkoxy, di[(1-2C)alkyl]amino or (2-7C)heterocycloalkyl;
R 135 is (2-7C)heterocycloalkyl, (1-6C)alkylamino, di[(1-6C)alkyl]amino, (2-7C)heterocycloalkylamino or (3-6C)cycloalkylamino each optionally substituted with one or more groups selected from (1-2C)alkyl, fluoro, hydroxyl, (1-2C)alkoxy, di[(1-2C)alkyl]amino, (2-7C)heterocycloalkyl, oxo, cyano or amino;
R 14 is H, halogen, (1-2C)alkyl or (1-2C)alkoxy; and
R 15 is H, halogen;
R 2 is selected from the group consisting of:
R 21 is H, halogen, (1-3C)alkyl, (1-2C)alkoxy, hydroxy(1-2C)alkyl, (3-4C)cycloalkyl, (2-3C)alkenyl or cyano;
R 22 is H, halogen, (1-2C)alkyl or (1-2C)alkoxy;
R 23 is H, halogen, (1-2C)alkyl, (1-2C)alkoxy, cyano or hydroxy;
R 24 is H, halogen, (1-2C)alkyl or (1-2C)alkoxy;
R 25 is H, halogen, (1-3C)alkyl, (1-2C)alkoxy, hydroxy(1-2C)alkyl, (3-4C)cycloalkyl, (2-3C)alkenyl or cyano;
R 26 is H, (1-6C)alkyl, (3-6C)cycloalkyl, (2-5C)heterocycloalkyl, (1-2C)alkoxy[(2-4C)alkoxy], (1-6C)alkyl, wherein n represents an integer of 1, 2, 3 or 4, all alkyl, heterocycloalkyl and (1-2C)alkoxy[(2-4C)alkoxy](1-6C)alkyl groups optionally substituted with one or more groups selected from (1-2C)alkyl, (1-2C)alkoxy, hydroxyl, oxo, amino, (3-6C)cycloalkyl, di[(1-2C)alkyl]amino or (2-5C)heterocycloalkyl; and wherein
in the above Formula I only one of R 21 and R 25 in R 2 can be H.
17. The method according to claim 1 , wherein in Formula I:
R 1 is
R 11 is (1-2C)alkoxy, the alkoxy optionally being substituted with one or more halogen;
R 12 is H;
R 13 is R 132 O, R 135 C(O), (2-7C)heterocycloalkyl, or (1-5C)heteroaryl each heterocycloalkyl or heteroaryl optionally being substituted with (1-2C)alkyl, (1-6C)alkylcarbonyl, or (2-7C)heterocycloalkylcarbonyl, each alkylcarbonyl or heterocycloalkylcarbonyl optionally being substituted with (1-2C)alkyl or (1-2C)alkoxy;
R 132 is (2-7C)heterocycloalkyl, optionally substituted with one or more groups selected from (1-2C)alkyl;
R 135 is (2-7C)heterocycloalkyl or (2-7C)heterocycloalkylamino, each optionally substituted with one or more groups selected from (1-2C)alkyl;
R 14 is H;
R 15 is H;
R 2 is selected from the group consisting of:
R 21 is (1-3C)alkyl;
R 22 is H;
R 23 is H;
R 24 is H;
R 25 is (1-3C)alkyl;
R 26 is H, (1-6C)alkyl, or (1-2C)alkoxy[(2-4C)alkoxy] n (1-6C)alkyl, wherein n represents an integer of 1, 2, 3 or 4.
18. The method according to claim 17 , wherein said mutation results in a substitution of one or more serine or threonine residues in the corresponding CTNNB1-encoded protein, or wherein said mutation is a deletion of one or more serine or threonine residues in the corresponding CTNNB1-encoded protein.
19. The method according to claim 18 , wherein said mutation results in a substitution of one or more serine or threonine residues in the corresponding CTNNB1-encoded protein at a position selected from S33, S37, S45 and T41, or wherein said mutation is a deletion of one or more serine or threonine residues in the corresponding CTNNB1-encoded protein at a position selected from S33, S37, S45 and T41.
20. The method according to claim 17 , wherein the mutation results in a substitution or a deletion of the serine residue corresponding to codon 33 of CTNNB1.
21. The method according to claim 17 , wherein the mutation results in a substitution or a deletion of the threonine residue corresponding to codon 41 of CTNNB1.
22. The method according to claim 17 , wherein the mutation results in a substitution or a deletion of the serine residue corresponding to codon 45 of CTNNB1.
23. The method according to claim 17 , wherein the mutation results in a substitution or a deletion of the serine residue corresponding to codon 37 of CTNNB1.