MATERIALS AND METHODS FOR SUPPRESSING AND/OR TREATING BONE RELATED DISEASES AND SYMPTOMS
Various aspects and embodiments disclosed herein relate generally to the modelling, treatment, reducing resistence to the treatment, prevention, and diagnosis of diseases/symptoms induced by multiple myeloma. Embodiments include methods of treating a bone related disease, comprising the steps of: administering to a subject at least one therapeutically effective dose of a compound disclosed herein.
1 . A compound comprising:
a compound of the formula A-Y-B; wherein:
A is at least one agent that reduces and/or inhibits the activitiy of gamma-secretase;
B is at least one bone-targeting molecule; and
Y is a linker that joins and/or links A and B;
or a pharmaceutically acceptable salt thereof, or a metabolite thereof.
2 . The compound of claim 1 , wherein:
A is the at least one agent that reduces and/or inhibits the activitiy of gamma-secretase;
Y is the linker comprising the formula NR 1 ;
R 1 is NR 2 R 3 , NR 2 S(=O) 2 R 3 or R 2 OR 3 ;
R 2 and R 3 are independently selected from H, C 1 -C 10 alkyl, C 1 -C 10 alkoxy, C 6 H 5 OR 4 , benzoyl isoleucine, leucine aldehyde, phenyl optionally substituted with C 1 -C 10 alkyl, C 1 -C 10 alkoxy, carbonyl, or amide, or benzyl optionally substituted with C 1 -C 10 alkyl, C 1 -C 10 alkoxy, carbonyl, or amide;
R 4 is C 1 -C 10 alkyl, C 1 -C 10 alkoxy, carbonyl, or amide; and
B is at least one bisphosphonate optionally substituted with OH, halogen, CH 3 , NH 2 , N-alkyl, or N-dialkyl;
or a pharmaceutically acceptable salt thereof, or a metabolite thereof.
3 . The compound according to any one of claims 1-2 , wherein A is a gamma-secretase inhibitor comprising the formula:
.
4 . The compound according to any one of claims 1-2 , wherein the compound comprises one or more stereoisomers of the formula:
wherein:
‘R is H, CH 3 , alkyl, halogen, CF 3 , CN, OH, OCH 3 , or O-alkyl;
n is 1-9;
m is 0-7; and
X is H, OH, halogen, CH 3 , NH 2 , N-alkyl, or N-dialkyl;
or a pharmaceutically acceptable salt thereof, or a metabolite thereof.
5 . The compound according to claim 4 , wherein n is 1-3, m is 0, and X is H.
6 . The compound according to any of the preceding claims, wherein said compound is a compound of formula:
or a pharmaceutically acceptable salt thereof, or a metabolite thereof.
7 . The compound according to according to claim 4 , wherein the one or more stereoisomers comprise any one or more of the formula:
.
8 . A method of reducing the growth of myeloma cells and/or osteoclast differentiation, comprising the steps of:
administering to a subject at least one therapeutically effective dose of a compound of any one of claims 1-7 or a pharmaceutically acceptable salt or metabolite thereof.
9 . The method according to claim 8 , further comprising the step of: administering to the subject at least one therapeutically effective dose of parathyroid hormone.
10 . The method according to any one of claims 8-9 , further comprising the step of: administering to the subject at least one therapeutically effective dose of at least one proteasome inhibitor.
11 . The method according to claim 10 , wherein the at least one proteasome inhibitor comprises lactacystin, disulfiram, epigallocatechin-3-gallate, marizomib (salinosporamide A), oprozomib (ONX-0912), delanzomib (CEP-18770), epoxomicin, beta-hydroxy beta-methylbutyrate, bortezomib, carfilzomib, and/or ixazomib.
12 . The method according to any one of claims 8-11 , wherein the subject comprises a human, an animal, a cell, and/or a tissue.
13 . A method of treating a bone related disease, comprising the steps of:
administering to a subject at least one therapeutically effective dose of a compound of any one of claims 1-7 or a pharmaceutically acceptable salt or metabolite thereof.
14 . The method according to claim 13 , further comprising the step of: administering to the subject at least one therapeutically effective dose of parathyroid hormone.
15 . The method according to any one of claims 13-14 , further comprising the step of: administering to the subject at least one therapeutically effective dose of at least one proteasome inhibitor.
16 . The method according to claim 15 , wherein the at least one proteasome inhibitor comprises lactacystin, disulfiram, epigallocatechin-3-gallate, marizomib (salinosporamide A), oprozomib (ONX-0912), delanzomib (CEP-18770), epoxomicin, beta-hydroxy beta-methylbutyrate, bortezomib, carfilzomib, and/or ixazomib.
17 . The method according to any one of claims 13-16 , wherein the bone related disease comprises osteopenia, osteoporosis, rheumatoid arthritis, hematologic, gastrointestinal and pulmonary disease, autoimmunity, transplant rejection, multiple myeloma, bone cancer, brain cancer, breast cancer, endocrine cancer, gastrointestinal cancer, gynecologic cancer, prostate cancer, head and neck cancer, hematologic cancer, lung cancer, renal cell carcinoma, skin cancer, urologic cancer, and/or rare cancer.
18 . The method according to any one of claims 13-17 , wherein the subject comprises a human, an animal, a cell, and/or a tissue.
19 . A method of treating a bone related disease, comprising the steps of:
administering to a subject at least one therapeutically effective dose of at least one agent that reduces and/or inhibits the activitiy of gamma-secretase, or a pharmaceutically acceptable salt or metabolite thereof, and at least one bisphosphonate, or a pharmaceutically acceptable salt or metabolite thereof.
20 . The method according to claim 19 , further comprising the step of: administering to the subject at least one therapeutically effective dose of parathyroid hormone.
21 . The method according to any one of claims 19-20 , further comprising the step of: administering to the subject at least one therapeutically effective dose of at least one proteasome inhibitor.
22 . The method according to claim 21 , wherein the at least one proteasome inhibitor comprises lactacystin, disulfiram, epigallocatechin-3-gallate, marizomib (salinosporamide A), oprozomib (ONX-0912), delanzomib (CEP-18770), epoxomicin, beta-hydroxy beta-methylbutyrate, bortezomib, carfilzomib, and/or ixazomib.
23 . The method according to any one of claims 19-22 , wherein the at least one agent that reduces and/or inhibits the activitiy of gamma-secretase comprises a compound having the formula:
.
24 . The method according to any one of claims 19-23 , wherein the bone related disease comprises osteopenia, osteoporosis, rheumatoid arthritis, hematologic, gastrointestinal and pulmonary disease, autoimmunity, transplant rejection, multiple myeloma, bone cancer, brain cancer, breast cancer, endocrine cancer, gastrointestinal cancer, gynecologic cancer, prostate cancer, head and neck cancer, hematologic cancer, lung cancer, renal cell carcinoma, skin cancer, urologic cancer, and/or rare cancer.
25 . The method according to any one of claims 19-24 , wherein the subject comprises a human, an animal, a cell, and/or a tissue.