Calmodulin inhibitors, chk2 inhibitors and rsk inhibitors for the treatment of ribosomal disorders and ribosomapathies

A method of treating a subject with a ribosomal disorder or ribosomopathy, comprising:

• (i) administering an effective amount of a composition comprising an inhibitor of ribosomal s6 kinase, RSK (p90S6k), to the subject to decrease p90S6K activity and decrease active p53 in at least one of CD34+ cells, erythroid cells or erythroid differentiated cells in the subject;
• (ii) administering an effective amount of a composition comprising an inhibitor of RSK (p70S6K) to the subject to decrease p70S6K activity and decrease active p53 in at least one of CD34+ cells, erythroid cells or erythroid differentiated cells in the subject;
• (iii) administering an effective amount of a composition comprising an inhibitor of Chk2 to the subject to decrease active p53 in at least one of CD34+ cells, erythroid cells or erythroid differentiated cells in the subject, wherein the inhibitor of Chk2 comprises a compound selected from the group consisting of CCT and III, or derivatives thereof, wherein CCT and III have the following structures:
• (iv) administering an effective amount of a composition comprising an inhibitor of calmodulin to the subject to decrease active p53 in at least one of CD34+ cells, erythroid cells or erythroid differentiated cells in the subject, wherein the inhibitor of calmodulin is a phenothiazine compound, or a derivative or analogue of the phenothiazine compound, wherein the phenothiazine compound is selected from the group consisting of ACV-1-235 (ACV), JJM-II-221E (221E) and DB1026(PerSucc), wherein ACV-1-235 (ACV), JJM-II-221E (221E) and DB1026(PerSucc) have the following structures:
• (v) administering an effective amount of a composition comprising a phenothiazine compound, or a derivative or analogue of the phenothiazine compound, wherein the phenothiazine compound is selected from the group consisting of DB-4-083 (083), DB-4-084 (084), DB-4-088-2 (088-2), DB-4-088-3 (088-3), DB-4-086 (086), DB-4-087-2 (087-2), DB-4-087-3 (087-3) and DB-4-089 (089), wherein DB-4-083 (083), DB-4-084 (084), DB-4-088-2 (088-2), DB-4-088-3 (088-3), DB-4-086 (086), DB-4-087-2 (087-2), DB-4-087-3 (087-3) and DB-4-089 (089) have the following structures
• (vi) administering an effective amount of a composition comprising a phenothiazine compound, or a derivative or analogue of the phenothiazine compound, wherein the phenothiazine compound is a compound of Formula (I):
• wherein:
• X is O or S;
• R1 is H, alkyl, alkenyl, alkynyl, cyclyl, heterocyclyls, acyl, aryl, heteroaryl, alkylheteroaryl or alkylaryl;
• each R is independently H, halo, alkyl, alkyl, alkenyl, alkynyl, haloalkyl, CN, OH, NH2, alkylamino, dialkylamino, CO2H, acyl, SH, thioalkoxy, SOH, or SO3H;
• and isomers and pharmaceutically acceptable salts thereof;
• (v) administering an effective amount of a composition comprising a a phenothiazine compound, or a derivative or analogue of the phenothiazine compound, wherein the phenothiazine compound is a compound of Formula (II):
• wherein:
• each R21 is independently selected from the group consisting of H, halo, alkyl, haloalkyl, CN, OH, NH2, alkylamino, dialkylamino, CO2H, acyl, SH, thioalkoxy, SO2H, and SO3H;
• isomers and pharmaceutically acceptable salts thereof;
• (vi) administering an effective amount a composition comprising a phenothiazine compound, or a derivative or analogue of the phenothiazine compound, wherein the phenothiazine compound is a compound of structure:
• or
• (vii) administering an effective amount of the is a calcium channel blocker BAPTA-AM or derivative or analogue thereof to the subject to decrease active p53 in at least one of CD34+ cells, wherein BAPTA-AM has the following structure: