Organic compositions to treat HSF1-related diseases

Patent metadata

Field	Value
Publication number	US-10287582-B2
Application number	US-201615359894-A
Country	US
Kind code	B2
Filing date	Nov 23, 2016
Priority date	Dec 18, 2009
Publication date	May 14, 2019
Grant date	May 14, 2019

Abstract

The present disclosure relates to methods of treating heat shock factor 1 (HSF1)-related diseases such as cancer and viral diseases, using a therapeutically effective amount of a RNAi agent to HSF.

First claim

We claim:

1. A composition comprising an RNAi agent to HSF1 comprising a first strand and a second strand, wherein the sequence of the first strand comprises SEQ ID NO: 678, wherein the first and/or second strand comprises at least one modified sugar backbone or 2′-modified nucleotide, wherein the first and/or second strand are no more than about 49 nt long, and wherein the first strand and the second strand are at least substantially complementary to each other.

2. The composition of claim 1 , wherein the composition further comprises a second RNAi agent to HSF1.

3. The composition of claim 1 , wherein the first strand and the second strand are both about 19 to about 23 nucleotides in length.

4. The composition of claim 1 , wherein the RNAi agent comprises a phosphorothioate linkage.

5. The composition of claim 1 , wherein the RNAi agent comprises a 2′-modification selected from the group consisting of: 2′-deoxy, 2′-deoxy-2′-fluoro, 2′-O-methyl, 2′-O-methoxyethyl (2′-O-MOE), 2′-O-aminopropyl (2′-O-AP), 2′-O-dimethylaminoethyl (2′-O-DMAOE), 2′-O-dimethylaminopropyl (2′-O-DMAP), 2′-O-dimethylaminoethyloxyethyl (2′-O-DMAEOE), and 2′-O—N-methylacetamido (2′-O-NMA).

6. The composition of claim 1 , wherein the RNAi agent comprises a blunt end or an overhang having 1 to 4 unpaired nucleotides.

7. The composition of claim 1 , wherein the RNAi agent is ligated to one or more diagnostic compound, reporter group, cross-linking agent, nuclease-resistance conferring moiety, natural or unusual nucleobase, lipophilic molecule, cholesterol, lipid, lectin, steroid, uvaol, hecigenin, diosgenin, terpene, triterpene, sarsasapogenin, Friedelin, epifriedelanol-derivatized lithocholic acid, vitamin, carbohydrate, dextran, pullulan, chitin, chitosan, synthetic carbohydrate, oligo lactate 15-mer, natural polymer, low- or medium-molecular weight polymer, inulin, cyclodextrin, hyaluronic acid, protein, protein-binding agent, integrin-targeting molecule, polycationic, peptide, polyamine, peptide mimic, and/or transferrin.

8. A composition comprising an RNAi agent to HSF1 comprising a first strand and a second strand, wherein the sequence of the first strand comprises the sequence of SEQ ID NO: 678, and the sequence of the second strand comprises the sequence of SEQ ID NO: 166, wherein the first and/or second strand comprises at least one modified sugar backbone or 2′-modified nucleotide, wherein the first and/or second strand are no more than about 49 nt long, and wherein the composition further comprises and a pharmaceutically acceptable carrier.

9. The composition of claim 8 , wherein the composition further comprises a second RNAi agent to HSF1.

10. The composition of claim 8 , wherein the first strand and the second strand are both 19 to 23 nucleotides in length.

11. The composition of claim 8 , wherein the RNAi agent comprises a phosphorothioate linkage.

12. The composition of claim 8 , wherein the RNAi agent comprises a 2′-modification selected from the group consisting of: 2′-deoxy, 2′-deoxy-2′-fluoro, 2′-O-methyl, 2′-O-methoxyethyl (2′-O-MOE), 2′-O-aminopropyl (2′-O-AP), 2′-O-dimethylaminoethyl (2′-O-DMAOE), 2′-O-dimethylaminopropyl (2′-O-DMAP), 2′-O-dimethylaminoethyloxyethyl (2′-O-DMAEOE), and 2′-O—N-methylacetamido (2′-O-NMA).

13. The composition of claim 8 , wherein the RNAi agent comprises a blunt end or an overhang having 1 to 4 unpaired nucleotides.

14. The composition of claim 8 , wherein the RNAi agent is ligated to one or more diagnostic compound, reporter group, cross-linking agent, nuclease-resistance conferring moiety, natural or unusual nucleobase, lipophilic molecule, cholesterol, lipid, lectin, steroid, uvaol, hecigenin, diosgenin, terpene, triterpene, sarsasapogenin, Friedelin, epifriedelanol-derivatized lithocholic acid, vitamin, carbohydrate, dextran, pullulan, chitin, chitosan, synthetic carbohydrate, oligo lactate 15-mer, natural polymer, low- or medium-molecular weight polymer, inulin, cyclodextrin, hyaluronic acid, protein, protein-binding agent, integrin-targeting molecule, polycationic, peptide, polyamine, peptide mimic, and/or transfenin.

15. A method of inhibiting the expression of HSF1 in an individual afflicted with an HSF1-related cancer, the method comprising administering to the individual a composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of an RNAi agent to HSF1 comprising a first strand and a second strand, wherein the sequence of the first strand comprises SEQ ID NO: 678, wherein the first and/or second strand comprises at least one modified sugar backbone or 2′-modified nucleotide, wherein the first and/or second strand are no more than about 49 nucleotides long, wherein the first strand and the second strand are at least substantially complementary to each other, and wherein the method optionally further comprises administering a second RNAi agent to HSF1.

16. The method of claim 15 , wherein the HSF1-related disease is cancer selected from the list of bladder, bone, breast, cervical, colon, colorectal, endometrial, fibrosarcoma, gastric, haematopoietic, intestine, kidney, liver, lung, lymphoma, neuroectodermal, neuroblastoma, Ewing's sarcoma, osteosarcoma, ovary, pancreas, pleura, prostate, skin, squamous cell, stomach, and testicular cancers, leukemia, promyelocytic leukemia, and Hodgkin's disease.

17. The method of claim 15 , wherein the method further comprises the step of administering one or more additional pharmaceutical agents.

18. The composition of claim 1 , further comprising one or more additional pharmaceutical agents.

Assignees

• Arrowhead Pharmaceuticals Inc

Inventors

• Hinkle Gregory
• Kuchimanchi Satyanarayana
• Milstein Stuart
• Warmuth Markus
• Zhou Wenlai
• Zhu Ping
• Zimmermann Tracy S

Classifications

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P35/04

  specific for metastasis · CPC title

• A61P37/08

  Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14) · CPC title