P38 kinase inhibitors reduce DUX4 and downstream gene expression for the treatment of FSHD

• US 10,537,560 B2
• Filed: 11/19/2018
• Issued: 01/21/2020
• Est. Priority Date: 10/05/2017
• Status: Active Grant

• Current Assignee: Fulcrum Therapeutics, Inc.
• Original Assignee: Fulcrum Therapeutics, Inc.
• Inventors: Cacace, Angela Marie, Rojas Soto, Luis Gustavo Alejandro, Thompson, III, Lorin A., Wallace, Owen Brendan, Ronco, Lucienne V., Shen, Ning, Robertson, Alan Scott, Chang, Aaron Nakwon
• Primary Examiner(s): Rao, Savitha M
• Application Number:
  US16/195,361
• Publication Number:
  US 20190105312A1
• Time in Patent Office: 428 Days
• CPC Class Codes: A61K 31/416 condensed with carbocyclic ring systems, e.g. indazole
• CPC Class Codes: A61K 31/437 the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
• CPC Class Codes: A61K 31/4418 having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
• CPC Class Codes: A61K 31/4439 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole nicotine A61K31/465
• CPC Class Codes: A61K 31/454 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/513 having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 31/53 having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine melarsoprol A61K31/555 ; with four nitrogen atoms A61K31/495
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61K 9/0053 Mouth and digestive tract, i.e. intraoral and peroral administration rectal administration A61K9/0031
• CPC Class Codes: A61K 9/0073 Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy; nasal sprays A61K9/0043; inhalation of vapours of volatile or heated drugs, e.g. essential oils or nicotine, A61K9/007; devices A61M
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: C12Q 1/6827 for detection of mutation or polymorphism
• CPC Class Codes: C12Q 1/686 Polymerase chain reaction [PCR]
• CPC Class Codes: C12Q 1/6883 for diseases caused by alterations of genetic material
• CPC Class Codes: C12Q 2600/106 Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
• CPC Class Codes: C12Q 2600/156 Polymorphic or mutational markers

Abstract

The disclosure relates to methods and compositions including p38 kinase inhibitors and agents that regulate expression of DUX4 and downstream genes including but not restricted to ZSCAN4, LEUTX, PRAMEF2, TRIM43, MBD3L2, KHDC1L, RFPL2, CCNA1, SLC34A2, TPRX1, PRAMEF20, TRIM49, PRAMEF4, PRAME6, PRAMEF15, or ZNF280A. Methods useful for treating a disease associated with abnormal DUX4 and downstream gene expression (e.g., Fascioscapulohumeral muscular dystrophy) are disclosed.

Claims

1. A method for treating facioscapulohumeral muscular dystrophy (FSHD), the method comprising administering to a subject in need thereof, an effective amount of a p38 kinase inhibitor,

wherein the p38 kinase inhibitor is selected from:

2. The method of claim 1, wherein the DUX4 downstream gene is selected from the group consisting of:

ZSCAN4, LEUTX, PRAMEF2, TRIM43, MBD3L2, KHDC1L, RFPL2, CCNA1, SLC34A2, TPRX1, PRAMEF20, TRIM49, PRAMEF4, PRAME6, PRAMEF15, and ZNF280A.

3. The method of claim 1, wherein the muscle cells are terminally differentiated muscle cells.

4. The method of claim 1, wherein the muscle cells comprise a dysregulated D4Z4 array at chromosome 4q35.

5. The method of claim 1, wherein the facioscapulohumeral muscular dystrophy is FSHD type 1 (FSHD1).

6. The method of claim 5, wherein the muscle cells comprise a deletion of one or more macrosatellite D4Z4 repeats in the subtelomeric region of chromosome 4q35.

7. The method of claim 6, wherein the muscle cell comprises less than 11 macrosatellite D4Z4 repeats in the subtelomeric region of chromosome 4q35.

8. The method of claim 1, wherein the facioscapulohumeral muscular dystrophy is FSHD type 2 (FSHD2).

9. The method of claim 8, wherein the muscle cells comprise one or more mutations in a Structural Maintenance Of Chromosomes Flexible Hinge Domain Containing 1 (SMCHD1) gene.

10. The method of claim 1, wherein the muscle cells comprise at least one non-deleted 4qA allele.

11. The method of claim 1, wherein the administering causes a decrease in muscle degeneration in the subject.

12. The method of claim 1, wherein the administering causes a reduction in apoptosis of muscle cells in the subject.

13. The method of claim 1, wherein the compound or the pharmaceutically acceptable salt thereof is administered to the subject parenterally.

14. The method of claim 1, wherein the compound or the pharmaceutically acceptable salt thereof is administered to the subject orally.

15. The method of claim 1, wherein the compound or the pharmaceutically acceptable salt thereof is administered to the subject via inhalation.

16. A method of reducing expression levels of a DUX4 polypeptide and/or a polypeptide encoded by a DUX4 downstream gene in muscle cells in a subject in need thereof, the method comprising administering to the subject, an effective amount of a p38 kinase inhibitor selected from:

17. The method of claim 16, wherein the DUX4 downstream gene is selected from the group consisting of:

ZSCAN4, LEUTX, PRAMEF2, TRIM43, MBD3L2, KHDC1L, RFPL2, CCNA1, SLC34A2, TPRX1, PRAMEF20, TRIM49, PRAMEF4, PRAME6, PRAMEF15, and ZNF280A.

18. The method of claim 16, wherein the muscle cells are terminally differentiated muscle cells.

19. The method of claim 16, wherein the muscle cells comprise a dysregulated D4Z4 array at chromosome 4q35.

20. The method of claim 16, wherein the muscle cells comprise a deletion of one or more macrosatellite D4Z4 repeats in the subtelomeric region of chromosome 4q35.

21. The method of claim 20, wherein the muscle cell comprises less than 11 macrosatellite D4Z4 repeats in the subtelomeric region of chromosome 4q35.

22. The method of claim 16, wherein the muscle cells comprise one or more mutations in a Structural Maintenance Of Chromosomes Flexible Hinge Domain Containing 1 (SMCHD1) gene.

23. The method of claim 16, wherein the muscle cells comprise at least one non-deleted 4qA allele.

24. The method of claim 16, wherein the administering causes a decrease in muscle degeneration in the subject.

25. The method of claim 16, wherein the administering causes a reduction in apoptosis of muscle cells in the subject.

26. The method of claim 16, wherein the compound or the pharmaceutically acceptable salt thereof is administered to the subject parenterally.

27. The method of claim 16, wherein the compound or the pharmaceutically acceptable salt thereof is administered to the subject orally.

28. The method of claim 16, wherein the compound or the pharmaceutically acceptable salt thereof is administered to the subject via inhalation.