Back to results
US 2024/0398767 A1Published application
Inhibitors of the mtdh-snd1 protein complex for cancer therapy
AssigneeThe Trustees of Princeton University
InventorsMinhong Shen, Hahn Kim, Yibin Kang
Life of this patent
Estimating the term…
Abstract
Provided herein are methods of using small molecule inhibitors of the MTDH-SND1 protein-protein interaction, such as a compound of the following structural formula: (I) or a pharmaceutically acceptable salt thereof, wherein values for the variables (e.g., X1, X2, X3, X4, X5, X6, X7, R3, R4, m) are as described herein. The compounds described herein can be used, for example, to treat cancer as, for example, by inhibiting metastasis of a cancer, sensitizing a cancer to treatment with an additional therapy, and/or promoting T-cell activation and/or infiltration in response to a cancer.
Claims55
A method of treating cancer in a subject in need thereof, comprising administering to the subject an effective amount of a compound of the following structural formula:
- or a pharmaceutically acceptable salt thereof, wherein:
- X1—X2—X3 is N—C(R20)—N, C(R10)—N—N, C(R10)—C(R20)—N, N—C(R20)—O, O—C(R20)—N, C(R10)—N—O, N—C(R20)—S, S—C(R20)—N, C(R10)—C(R20)—O, N(R11)—C(R20)—N or N(H)—C(O)—O;
- R10 is H, OH, halo, cyano, carboxy, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, amino, (C1-C6)alkylamino, (C1-C6)dialkylamino, (C3-C10)cycloalkyl, (C3-C10)heterocyclyl, (C6-C10)aryl, carboxy(C6-C10)aryl or (C5-C10)heteroaryl;
- R11 is H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C10)cycloalkyl, (C3-C10)heterocyclyl, (C6-C10)aryl or (C5-C10)heteroaryl;
- R20 is H, OH, halo, cyano, carboxy, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, amino, (C1-C6)alkylamino, (C1-C6)dialkylamino, (C3-C10)cycloalkyl, (C3-C10)heterocyclyl, (C6-C10)aryl, carboxy(C6-C10)aryl or (C5-C10)heteroaryl;
- X4, X5 and X6 are each independently C(H) or N;
- X7 is C or N;
- each R3 is independently hydroxy, halo, cyano, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, amino, (C1-C6)alkylamino, (C1-C6)dialkylamino, —C(O)R30, (C3-C10)cycloalkyl, (C3-C10)heterocyclyl, (C6-C10)aryl or (C5-C10)heteroaryl;
- each R30 is independently hydroxy, (C1-C6)alkoxy, amino, (C1-C6)alkylamino or (C1-C6)dialkylamino;
- R4 is (C3-C10)cycloalkyl, (C3-C10)heterocyclyl, (C6-C10)aryl or (C5-C10)heteroaryl optionally substituted with one or more R40;
- R40, for each occurrence, is independently halo, cyano, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy(C1-C6)alkoxy, carboxy(C1-C6)alkoxy, HO—N(H)C(O)—(C1-C6)alkoxy, HOS(O)2—(C1-C6)alkoxy, H2NS(O)2—(C1-C6)alkoxy, P(O)(OH)2—(C1-C6)alkoxy, P(O)(OH)(H)—(C1-C6)alkoxy, (HO)2B—(C1-C6)alkoxy, tetrazole-(C1-C6)alkoxy, thiazolidinedione-(C1-C6)alkoxy, oxazolidinedione-(C1-C6)alkoxy, isothiazole-(C1-C6)alkoxy, isoxazole-(C1-C6)alkoxy, oxooxadiazole-(C1-C6)alkoxy, oxothiadiazole-(C1-C6)alkoxy, thioxooxadiazole-(C1-C6)alkoxy, (C1-C6)alkoxy, (C1-C6)haloalkoxy, amino, (C1-C6)alkylamino, (C1-C6)dialkylamino, —C(O)R41, (C3-C10)cycloalkyl, (C3-C10)heterocyclyl, (C6-C10)aryl or (C5-C10)heteroaryl;
- or
- two R40 on adjacent atoms of R4, taken together with the atoms to which they are attached, form a 5- or 6-membered cycle optionally substituted with one or more R42;
- R41 is (C1-C6)alkoxy, amino, (C1-C6)alkylamino or (C1-C6)dialkylamino;
- R42, for each occurrence, is independently oxo or halo, cyano, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy or (C1-C6)haloalkoxy;
- and
- m is 0, 1, 2 or 3.
14 more elements
A method of inhibiting metastasis of a cancer in a subject having the cancer;
- sensitizing a cancer in a subject in need thereof to treatment with a radiation therapy, chemotherapy or immune therapy;
- or promoting T-cell activation or infiltration or both in response to a cancer in a subject in need thereof, comprising administering to the subject an effective amount of a compound of the following structural formula:
- or a pharmaceutically acceptable salt thereof, wherein:
- X1—X2—X3 is N—C(R20)—N, C(R10)—N—N, C(R10)—C(R20)—N, N—C(R20)—O, O—C(R20)—N, C(R10)—N—O, N—C(R20)—S, S—C(R20)—N, C(R10)—C(R20)—O, N(R11)—C(R20)—N or N(H)—C(O)—O;
- R10 is H, OH, halo, cyano, carboxy, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, amino, (C1-C6)alkylamino, (C1-C6)dialkylamino, (C3-C10)cycloalkyl, (C3-C10)heterocyclyl, (C6-C10)aryl, carboxy(C6-C10)aryl or (C5-C10)heteroaryl;
- R11 is H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C10)cycloalkyl, (C3-C10)heterocyclyl, (C6-C10)aryl or (C5-C10)heteroaryl;
- R20 is H, OH, halo, cyano, carboxy, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, amino, (C1-C6)alkylamino, (C1-C6)dialkylamino, (C3-C10)cycloalkyl, (C3-C10)heterocyclyl, (C6-C10)aryl, carboxy(C6-C10)aryl or (C5-C10)heteroaryl;
- X4, X5 and X6 are each independently C(H) or N;
- X7 is C or N;
- each R3 is independently hydroxy, halo, cyano, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, amino, (C1-C6)alkylamino, (C1-C6)dialkylamino, —C(O)R30, (C3-C10)cycloalkyl, (C3-C10)heterocyclyl, (C6-C10)aryl or (C5-C10)heteroaryl;
- each R30 is independently hydroxy, (C1-C6)alkoxy, amino, (C1-C6)alkylamino or (C1-C6)dialkylamino;
- R4 is (C3-C10)cycloalkyl, (C3-C10)heterocyclyl, (C6-C10)aryl or (C5-C10)heteroaryl optionally substituted with one or more R40;
- R40, for each occurrence, is independently halo, cyano, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy(C1-C6)alkoxy, carboxy(C1-C6)alkoxy, HO—N(H)C(O)—(C1-C6)alkoxy, HOS(O)2—(C1-C6)alkoxy, H2NS(O)2—(C1-C6)alkoxy, P(O)(OH)2—(C1-C6)alkoxy, P(O)(OH)(H)—(C1-C6)alkoxy, (HO)2B—(C1-C6)alkoxy, tetrazole-(C1-C6)alkoxy, thiazolidinedione-(C1-C6)alkoxy, oxazolidinedione-(C1-C6)alkoxy, isothiazole-(C1-C6)alkoxy, isoxazole-(C1-C6)alkoxy, oxooxadiazole-(C1-C6)alkoxy, oxothiadiazole-(C1-C6)alkoxy, thioxooxadiazole-(C1-C6)alkoxy, (C1-C6)alkoxy, (C1-C6)haloalkoxy, amino, (C1-C6)alkylamino, (C1-C6)dialkylamino, —C(O)R41, (C3-C10)cycloalkyl, (C3-C10)heterocyclyl, (C6-C10)aryl or (C5-C10)heteroaryl;
- or
- two R40 on adjacent atoms of R4, taken together with the atoms to which they are attached, form a 5- or 6-membered cycle optionally substituted with one or more R42;
- R41 is (C1-C6)alkoxy, amino, (C1-C6)alkylamino or (C1-C6)dialkylamino;
- R42, for each occurrence, is independently oxo or halo, cyano, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy or (C1-C6)haloalkoxy;
- and
- m is 0, 1, 2 or 3.
16 more elements
A method of inhibiting an interaction between metadherin (MTDH) and Staphylococcal nuclease domain containing 1 (SND1) in a cell expressing MTDH and SND1;
- or (i) stabilizing or increasing the level or expression of transporter associated with antigen processing (TAP), (ii) inhibiting degradation of Tap, or (iii) promoting tumor antigen presentation in a cell, the method comprising contacting the cell with a compound of the following structural formula:
- or a pharmaceutically acceptable salt thereof, wherein:
- X1—X2—X3 is N—C(R20)—N, C(R10)—N—N, C(R10)—C(R20)—N, N—C(R20)—O, O—C(R20)—N, C(R10)—N—O, N—C(R20)—S, S—C(R20)—N, C(R10)—C(R20)—O, N(R11)—C(R20)—N or N(H)—C(O)—O;
- R10 is H, OH, halo, cyano, carboxy, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, amino, (C1-C6)alkylamino, (C1-C6)dialkylamino, (C3-C10)cycloalkyl, (C3-C10)heterocyclyl, (C6-C10)aryl, carboxy(C6-C10)aryl or (C5-C10)heteroaryl;
- R11 is H, (C1-C6)alkyl, (C1-C6)haloalkyl, (C3-C10)cycloalkyl, (C3-C10)heterocyclyl, (C6-C10)aryl or (C5-C10)heteroaryl;
- R20 is H, OH, halo, cyano, carboxy, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, amino, (C1-C6)alkylamino, (C1-C6)dialkylamino, (C3-C10)cycloalkyl, (C3-C10)heterocyclyl, (C6-C10)aryl, carboxy(C6-C10)aryl or (C5-C10)heteroaryl;
- X4, X5 and X6 are each independently C(H) or N;
- X7 is C or N;
- each R3 is independently hydroxy, halo, cyano, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, amino, (C1-C6)alkylamino, (C1-C6)dialkylamino, —C(O)R30, (C3-C10)cycloalkyl, (C3-C10)heterocyclyl, (C6-C10)aryl or (C5-C10)heteroaryl;
- each R30 is independently hydroxy, (C1-C6)alkoxy, amino, (C1-C6)alkylamino or (C1-C6)dialkylamino;
- R4 is (C3-C10)cycloalkyl, (C3-C10)heterocyclyl, (C6-C10)aryl or (C5-C10)heteroaryl optionally substituted with one or more R40;
- R40, for each occurrence, is independently halo, cyano, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy(C1-C6)alkoxy, carboxy(C1-C6)alkoxy, HO—N(H)C(O)—(C1-C6)alkoxy, HOS(O)2—(C1-C6)alkoxy, H2NS(O)2—(C1-C6)alkoxy, P(O)(OH)2—(C1-C6)alkoxy, P(O)(OH)(H)—(C1-C6)alkoxy, (HO)2B—(C1-C6)alkoxy, tetrazole-(C1-C6)alkoxy, thiazolidinedione-(C1-C6)alkoxy, oxazolidinedione-(C1-C6)alkoxy, isothiazole-(C1-C6)alkoxy, isoxazole-(C1-C6)alkoxy, oxooxadiazole-(C1-C6)alkoxy, oxothiadiazole-(C1-C6)alkoxy, thioxooxadiazole-(C1-C6)alkoxy, (C1-C6)alkoxy, (C1-C6)haloalkoxy, amino, (C1-C6)alkylamino, (C1-C6)dialkylamino, —C(O)R41, (C3-C10)cycloalkyl, (C3-C10)heterocyclyl, (C6-C10)aryl or (C5-C10)heteroaryl;
- or
- two R40 on adjacent atoms of R4, taken together with the atoms to which they are attached, form a 5- or 6-membered cycle optionally substituted with one or more R42;
- R41 is (C1-C6)alkoxy, amino, (C1-C6)alkylamino or (C1-C6)dialkylamino;
- R42, for each occurrence, is independently oxo or halo, cyano, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy or (C1-C6)haloalkoxy;
- and
- m is 0, 1, 2 or 3.
15 more elements
A compound represented by the following structural formula:
- or a pharmaceutically acceptable salt thereof, wherein:
- X1 is N and X2 is C(R20);
- R20 is H, OH, halo, cyano, carboxy, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy, (C1-C6)haloalkoxy, amino, (C1-C6)alkylamino, (C1-C6)dialkylamino, (C3-C10)cycloalkyl, (C3-C10)heterocyclyl, (C6-C10)aryl, carboxy(C6-C10)aryl or (C5-C10)heteroaryl;
- R1 is (C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkyl, carboxy(C1-C6)alkyl, HO—N(H)C(O)—(C1-C6)alkyl, HOS(O)2—(C1-C6)alkyl, H2NS(O)2—(C1-C6)alkyl, P(O)(OH)2—(C1-C6)alkyl, P(O)(OH)(H)—(C1-C6)alkyl, (HO)2B—(C1-C6)alkyl, tetrazole-(C1-C6)alkyl, thiazolidinedione-(C1-C6)alkyl, oxazolidinedione-(C1-C6)alkyl, isothiazole-(C1-C6)alkyl, isoxazole-(C1-C6)alkyl, oxooxadiazole-(C1-C6)alkyl, oxothiadiazole-(C1-C6)alkyl or thioxooxadiazole-(C1-C6)alkyl;
- R2 is halo, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy or (C1-C6)haloalkoxy;
- each R3 is independently halo;
- R12 is hydrogen or R1 and R12, taken together with their intervening atoms, form a 5- or 6-membered cycle optionally substituted with one or more R22;
- R22, for each occurrence, is independently oxo or halo, cyano, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)alkoxy or (C1-C6)haloalkoxy;
- and
- m is 0, 1, 2 or 3, provided (i) R1 is not methyl;
- or (ii) the compound is not
- or a pharmaceutically acceptable salt thereof.
9 more elements
A nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:1, or a nucleotide sequence having at least 75%, at least 85%, at least 90% or at least 95% identity to the nucleotide sequence of SEQ ID NO:1.
A protein comprising the amino acid sequence of SEQ ID NO:2, or an amino acid sequence having at least 75%, at least 85%, at least 90% or at least 95% identity to the amino acid sequence of SEQ ID NO:2.
A nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:3, or a nucleotide sequence having at least 75%, at least 85%, at least 90% or at least 95% identity to the nucleic acid sequence of SEQ ID NO:3.
A protein comprising the amino acid sequence of SEQ ID NO:4, or an amino acid sequence having at least 75%, at least 85%, at least 90% or at least 95% identity to the amino acid sequence of SEQ ID NO:4.
Dependencies are inferred from the claim text.