Anti-cancer nuclear hormone receptor-targeting compounds
The disclosure relates to anti-cancer compounds derived from a payload which binds to poly(ADP-ribose) polymerase (PARP) and a nuclear steroid-targeting epitope (B of Formula I), which components are covalently linked via a linker, to products containing the same, as well as to methods of their use and preparation.
1. A compound of Formula A-L-B, wherein:
A is A1 or A4, wherein:
L is L1, L2, L3, L4, L5, L6, L7, L8, L9, L10, L11, L12, L13, L14, L15, L16, L17, L18, L19, L20, L21, L22, L23, L24, L25, L26, L27, L28, L29, L30, L31, L32, L33, L34, L35, L36, L37, L38, L39, L40, L41, L42, L43, L44, L45, or L46, wherein:
and;
B is B1, B2, B3, B4, B5, B6, B7, B8, B9, B10, B11, B12, B13, B14, B4-5-B16, B17, B18, or B19, wherein:
and further wherein the “*” in A1 and A4 and each L moiety denotes a covalent bond therebetween, and the wavy line in each L and B denotes a covalent bond therebetween;
wherein the compound of Formula A-L-B is selected from:
A1-L1-B1
A1-L1-B2
A1-L1-B3
A1-L1-B4
A1-L1-B5
A1-L1-B6
A1-L1-B7
A1-L1-B8
A1-L1-B9
A1-L1-B10
A1-L1-B11
A1-L1-B12
A1-L1-B13
A1-L2-B1
A1-L2-B2
A1-L2-B3
A1-L2-B4
A1-L2-B5
A1-L2-B6
A1-L2-B7
A1-L2-B8
A1-L2-B9
A1-L2-B10
A1-L2-B11
A1-L2-B12
A1-L2-B13
A1-L3-B1
A1-L3-B2
A1-L3-B3
A1-L3-B4
A1-L3-B5
A1-L3-B6
A1-L3-B7
A1-L3-B8
A1-L3-B9
A1-L3-B10
A1-L3-B11
A1-L3-B12
A1-L3-B13
A1-L4-B1
A1-L4-B2
A1-L4-B3
A1-L4-B4
A1-L4-B5
A1-L4-B6
A1-L4-B7
A1-L4-B8
A1-L4-B9
A1-L4-B10
A1-L4-B11
A1-L4-B12
A1-L4-B13
A1-L5-B1
A1-L5-B2
A1-L5-B3
A1-L5-B4
A1-L5-B5
A1-L5-B6
A1-L5-B7
A1-L5-B8
A1-L5-B9
A1-L5-B10
A1-L5-B11
A1-L5-B12
A1-L5-B13
A1-L6-B1
A1-L6-B2
A1-L6-B3
A1-L6-B4
A1-L6-B5
A1-L6-B6
A1-L6-B7
A1-L6-B8
A1-L6-B9
A1-L6-B10
A1-L6-B11
A1-L6-B12
A1-L6-B13
A1-L7-B1
A1-L7-B2
A1-L7-B3
A1-L7-B4
A1-L7-B5
A1-L7-B6
A1-L7-B7
A1-L7-B8
A1-L7-B9
A1-L7-B10
A1-L7-B11
A1-L7-B12
A1-L7-B13
A1-L8-B1
A1-L8-B2
A1-L8-B3
A1-L8-B4
A1-L8-B5
A1-L8-B6
A1-L8-B7
A1-L8-B8
A1-L8-B9
A1-L8-B10
A1-L8-B11
A1-L8-B12
A1-L8-B13
A1-L9-B1
A1-L9-B2
A1-L9-B3
A1-L9-B7
A1-L9-B8
A1-L9-B9
A1-L9-B11
A1-L9-B13
A1-L20-B1
A1-L20-B2
A1-L20-B3
A1-L20-B4
A1-L20-B5
A1-L20-B6
A1-L20-B7
A1-L20-B8
A1-L20-B9
A1-L20-B10
A1-L20-B11
A1-L20-B12
A1-L20-B13
A1-L21-B1
A1-L21-B2
A1-L21-B3
A1-L21-B4
A1-L21-B5
A1-L21-B6
A1-L21-B7
A1-L21-B8
A1-L21-B9
A1-L21-B10
A1-L21-B11
A1-L21-B12
A1-L21-B13
A1-L22-B1
A1-L22-B2
A1-L22-B3
A1-L22-B4
A1-L22-B5
A1-L22-B6
A1-L22-B7
A1-L22-B8
A1-L22-B9
A1-L22-B10
A1-L22-B11
A1-L22-B12
A1-L22-B13
A1-L23-B1
A1-L23-B2
A1-L23-B3
A1-L23-B4
A1-L23-B5
A1-L23-B6
A1-L23-B7
A1-L23-B8
A1-L23-B9
A1-L23-B10
A1-L23-B11
A1-L23-B12
A1-L23-B13
A1-L24-B1
A1-L24-B2
A1-L24-B3
A1-L24-B4
A1-L24-B5
A1-L24-B6
A1-L24-B7
A1-L24-B8
A1-L24-B9
A1-L24-B10
A1-L24-B11
A1-L24-B12
A1-L24-B13
A1-L30-B1
A1-L30-B2
A1-L30-B3
A1-L30-B4
A1-L30-B5
A1-L30-B6
A1-L30-B7
A1-L30-B8
A1-L30-B9
A1-L30-B10
A1-L30-B11
A1-L30-B12
A1-L30-B13
A1-L31-B1
A1-L31-B2
A1-L31-B3
A1-L31-B4
A1-L31-B5
A1-L31-B6
A1-L31-B7
A1-L31-B8
A1-L31-B9
A1-L31-B10
A1-L31-B11
A1-L31-B12
A1-L31-B13
A1-L32-B1
A1-L32-B2
A1-L32-B3
A1-L32-B7
A1-L32-B8
A1-L32-B9
A1-L32-B11
A1-L32-B13
A1-L39-B1
A1-L39-B2
A1-L39-B3
A1-L39-B4
A1-L39-B5
A1-L39-B6
A1-L39-B7
A1-L39-B8
A1-L39-B9
A1-L39-B10
A1-L39-B11
A1-L39-B12
A1-L39-B13
A1-L40-B1
A1-L40-B2
A1-L40-B3
A1-L40-B4
A1-L40-B5
A1-L40-B6
A1-L40-B7
A1-L40-B8
A1-L40-B9
A1-L40-B10
A1-L40-B11
A1-L40-B12
A1-L40-B13
A1-L41-B1
A1-L41-B2
A1-L41-B3
A1-L41-B4
A1-L41-B5
A1-L41-B6
A1-L41-B7
A1-L41-B8
A1-L41-B9
A1-L41-B10
A1-L41-B11
A1-L41-B12
A1-L41-B13
A1-L42-B1
A1-L42-B2
A1-L42-B3
A1-L42-B4
A1-L42-B5
A1-L42-B6
A1-L42-B7
A1-L42-B8
A1-L42-B9
A1-L42-B10
A1-L42-B11
A1-L42-B12
A1-L42-B13
A1-L43-B1
A1-L43-B2
A1-L43-B3
A1-L43-B4
A1-L43-B5
A1-L43-B6
A1-L43-B7
A1-L43-B8
A1-L43-B9
A1-L43-B10
A1-L43-B11
A1-L43-B12
A1-L43-B13
A1-L44-B1
A1-L44-B2
A1-L44-B3
A1-L44-B7
A1-L44-B8
A1-L44-B9
A1-L44-B11
A1-L44-B13
A1-L20-B14
A1-L21-B14
A1-L22-B14
A1-L23-B14
A1-L24-B14
A1-L2-B14
A1-L3-B14
A1-L45-B14
A1-L20-B16
A1-L21-B16
A1-L22-B16
A1-L23-B16
A1-L24-B16
A1-L2-B16
A1-L3-B16
A1-L45-B16
A1-L20-B17
A1-L21-B17
A1-L22-B17
A1-L23-B17
A1-L24-B17
A1-L2-B17
A1-L3-B17
A1-L45-B17
A1-L20-B18
A1-L21-B18
A1-L22-B18
A1-L23-B18
A1-L24-B18
A1-L2-B18
A1-L3-B18
A1-L45-B18
A1-L20-B19
A1-L21-B19
A1-L22-B19
A1-L23-B19
A1-L24-B19
A1-L2-B19
A1-L3-B19
A1-L45-B19
A4-L46-B10
A4-L18-B10
A4-L19-B10
A4-L46-B16
A4-L18-B16
A4-L19-B16
A4-L46-B6
A4-L18-B6
A4-L19-B6 and
A1-L45-B10
or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog or pharmaceutically acceptable salt thereof.
2. The compound of claim 1 , wherein the compound is selected from:
or a stereoisomer, mixture of stereoisomers, hydrate, solvate, isotopically enriched analog or pharmaceutically acceptable salt thereof.
3. The compound of claim 1 , wherein the compound is selected from:
or a pharmaceutically acceptable salt thereof.
4. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient.
5. A method of treating an androgen receptor overexpressing cancer, comprising administering an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, to an individual in need thereof.
6. The method of claim 5 , wherein the cancer is prostate, breast, triple negative breast cancer, bladder, or liver cancer.
7. A method of treating an estrogen and/or progesterone receptor overexpressing cancer, comprising administering an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, to an individual in need thereof.
8. The method of claim 7 , wherein the cancer is breast, uterine, or ovarian cancer.
9. A method of treating a glucocorticoid receptor overexpressing cancer, comprising administering an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, to an individual in need thereof.
10. The method of claim 9 , wherein the cancer is prostate, breast, uterine, or ovarian cancer.