SETBP1 and XPO1 inhibitors for the treatment of sickle cell disease and β-thalassemia
The present disclosure relates to compounds that inhibit SETBP1 or XP01 activities. Also disclosed are methods of using such compounds to increase the expression of embryonic and fetal hemoglobin molecules, and to treat sickle cell disease and β-thalassemia. The present invention relates to unexpected findings that transcription factor SETBP1 regulates embryonic and fetal hemoglobin repression, and inhibition of SETBP1 can induce the expression of embryonic and fetal hemoglobins.
1 . A method of inducing embryonic or fetal hemoglobin expression in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a SETBP1 inhibitor, wherein the SETBP1 inhibitor is a compound of Formula (1A) or Formula (1B):
wherein X is selected from the group consisting of F, Cl, Br, and I,
wherein the subject is identified with a condition treatable by expression of embryonic and fetal hemoglobin.
2 . The method of claim 1 , wherein the SETBP1 inhibitor is a compound of Formula (1A):
wherein X is selected from the group consisting of F, Cl, Br, and I.
3 . The method of claim 1 , wherein the SETBP1 inhibitor is Compound (1AA)
4 . The method of claim 1 , wherein the SETBP1 inhibitor is a compound of Formula (1B):
wherein X is selected from the group consisting of F, Cl, Br, and I.
5 . The method of claim 1 , wherein the SETBP1 inhibitor is Compound (1BB):
6 . The method of claim 1 , wherein the condition is sickle cell disease (SCD) or β-thalassemia.
7 . The method of claim 1 , further comprising administering a XPO1 inhibitor selected from the group consisting of KPT-185, KPT-276, KPT-330, KPT-335, and KPT-8602.