CROSS-REFERENCE TO RELATED APPLICATIONS

This application is the National Stage of International Patent Application No. PCT/EP2016/076550, filed Nov. 3 2016, which claims the benefit of Swedish application number 1551419-3, filed Nov. 3, 2015, the disclosures of which are incorporated herein by reference in their entireties.

FIELD OF INVENTION

The present invention relates to the field of treatment of ribosomopathies, and conditions characterized by reduced number of hematopoietic stem cells and/or progenitor cells. The invention also relates to treatment of disorders that can be improved by increasing bone formation. The invention discloses that CDK8 and/or CDK19 inhibitors may be useful in treatment of such disorders.

BACKGROUND OF INVENTION

Diamond-Blackfan Anemia (DBA) can be considered as a ribosomopathy model indication. It is caused by mono-allelic inactivating mutations in ribosomal protein genes causing disturbed ribosome biogenesis. DBA is a pure red blood cell aplasia, characterized by severely decreased numbers of erythropoietin-responsive red blood cell precursors. DBA Patients are currently treated with blood transfusions or corticosteroids, therapies that are associated with severe adverse effects and treatment-related death (Blood. 2010 Nov. 11; 116(19):3715-23). Shwachman-Diamond Syndrome (SDS) is an example of another ribosomopathy caused by bi-allelic hypomorphic mutations in the SBDS gene that leads to disturbed maturation of the large ribosomal subunit (Ann N Y Acad Sci. 2011 December 1242:40-55). DBA and SDS are merely two out of several other “Ribosomopathies” caused by failed ribosome biogenesis. The mechanisms behind the symptoms such as bone marrow failure in these syndromes are poorly understood but are likely related to consequences of dysregulation of mRNA translation and/or failure in ribosome biogenesis which may induce activation of stress responses. Treatment options are limited for these diseases and new mechanism-based therapies are needed.

SUMMARY OF INVENTION

The present inventors have discovered that the enzymes cyclin-dependent kinase 8 (CDK8) and cyclin-dependent kinase 19 (CDK19) play a key role in the etiology of ribosomopathies and disorders characterized by reduced number of hematopoietic stem cells and/or progenitor cells, as well as in bone anabolic disorders.

Thus in a main aspect the present invention concerns a compound for use in the treatment of an indication selected from the group consisting of ribosomopathy; a disease characterized by reduced number of hematopoietic stem cells and/or progenitor cells; and bone anabolic disorders wherein the compound is an inhibitor of cyclin-dependent kinase 8 (CDK8) and/or cyclin-dependent kinase 19 (CDK19).

