Calmodulin inhibitors, Chk2 inhibitors and RSK inhibitors for the treatment of ribosomal disorders and ribosomapathies
The present invention relates to methods, compositions and kits for treatment of ribosomal disorders and ribosomopathies, e.g. Diamond Blackfan anemia (DBA). In some embodiments, the invention relates to the use of novel classes of compounds, i.e. inhibitors of RSK (p90S6K); inhibitors of p70S6K; and inhibitors of rps6, to treat ribosomal disorders and ribosomopathies. In some embodiments, the invention relates to the use of specific Chk2 inhibitors and to the use of specific phenothiazine derivatives to treat ribosomal disorders and ribosomopathies, e.g. DBA.
1. A method of treating a subject with Diamond Blackfan Anemia (DBA), comprising:
administering an effective amount of a composition comprising a phenothiazine compound, wherein the phenothiazine compound is selected from the group consisting of a compound of Formula (I), a compound of Formula (II), DB-4-083 (083), DB-4-084 (084), DB-4-088-3 (088-3), DB-4-086 (086), DB-4-087-2 (087-2), and DB-4-087-3 (087-30), wherein Formula (I), Formula (II), DB-4-083 (083), DB-4-084 (084), DB-4-088-3 (088-3), DB-4-086 (086), DB-4-087-2 (087-2), and DB-4-087-3 (087-3) have the following structures:
wherein:
X is S;
R 1 is ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, pentyl, neopentyl, hexyl, H, alkenyl, alkynyl, cyclyl, heterocyclyls, acyl, aryl, heteroaryl, alkylheteroaryl or alkylaryl;
each R is independently H, halo, alkyl, alkenyl, alkynyl, haloalkyl, CN, OH, NH 2 , alkylamino, dialkylamino, CO 2 H, acyl, SH, thioalkoxy, SO 2 H, or SO 3 H; and
pharmaceutically acceptable salts thereof; and
wherein:
each R 21 is independently selected from the group consisting of H, halo, alkyl, haloalkyl, CN, OH, NH 2 , alkylamino, dialkylamino, CO 2 H, acyl, SH, thioalkoxy, SO 2 H, and SO 3 H;
and pharmaceutically acceptable salts thereof.
2. The method of claim 1 , wherein the subject has a mutation in ribosomal protein 19 (RPS19).
3. The method of claim 1 , wherein the subject is administered another therapeutic agent to treat a ribosomal protein defect, selected from the group consisting of: corticosteroids and blood transfusions.
4. The method of claim 1 , wherein the subject has a symptom of macrocytic anemia or craniofacial abnormalities.
5. The method of claim 1 , wherein subject has a symptom selected from: the group consisting of pancreatic insufficiency, bone marrow dysfunction, and skeletal deformities.
6. The method of claim 1 , wherein the subject has a symptom of craniofacial deformities.
7. The method of claim 1 , wherein the phenothiazine compound is a compound of Formula (I).
8. The method of claim 1 , wherein the phenothiazine compound is selected from the group consisting of
9. The method of claim 1 , wherein the phenothiazine compound is