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Innovative HDAC Inhibitors for Targeted Cancer and Epigenetic Therapy

Introduction

Cancer treatment has evolved significantly, but many therapies still face challenges in targeting cancer cells selectively while sparing healthy tissue. Histone deacetylase (HDAC) inhibitors represent a promising approach, as they regulate gene expression by modifying chromatin structure, offering a powerful tool in the fight against cancer and other diseases driven by epigenetic factors. Our patented HDAC inhibitors introduce an innovative approach to targeting cancer cells by restoring the normal expression of tumor suppressor genes and disrupting cancer cell survival mechanisms. These inhibitors hold the potential to improve cancer treatment outcomes while minimizing side effects.

The Growing Need for Targeted Cancer Therapies

Traditional cancer therapies like chemotherapy and radiation often result in significant collateral damage, affecting healthy cells and causing severe side effects. While targeted therapies are a step in the right direction, many cancer types continue to evade treatment, develop resistance, or require more precision in their molecular targeting. Additionally, emerging research shows that gene expression regulation plays a key role in many diseases, particularly cancers where epigenetic modifications contribute to tumor growth and progression. This highlights the need for therapies that directly target epigenetic mechanisms, offering a more tailored approach to disease management.

Why HDAC Inhibitors are Critical for Future Therapies

Our patented HDAC inhibitors work by altering the acetylation state of histones, leading to changes in gene expression that can restore the function of tumor suppressor genes or inhibit oncogenic pathways. By targeting the epigenetic machinery, these inhibitors provide a more specific, less toxic approach to treating cancer. This technology has the potential to be combined with other cancer therapies, such as immunotherapy, enhancing their effectiveness while reducing overall toxicity.

Moreover, the inhibitors’ ability to affect gene expression extends beyond oncology, making them valuable in treating neurological disorders, autoimmune diseases, and other conditions linked to gene regulation abnormalities.

Key Benefits of Licensing This Technology

  • Targeted Epigenetic Therapy: These HDAC inhibitors selectively modify gene expression, offering a precise and less toxic alternative to traditional cancer treatments.
  • Broad Therapeutic Potential: Beyond oncology, this technology may be applied to neurological, autoimmune, and other epigenetically driven diseases.
  • Combination Therapy: Can be paired with existing treatments like chemotherapy or immunotherapy to enhance efficacy and reduce side effects.
  • Novel Mechanism of Action: Targets the root cause of disease progression by regulating gene expression, addressing unmet needs in cancer therapy.

Unlocking New Potential in Cancer Treatment and Beyond

Licensing this HDAC inhibitor technology provides pharmaceutical companies with the opportunity to lead in the development of next-generation cancer therapies and epigenetic treatments. Its broad therapeutic potential, combined with its precision in gene expression regulation, opens the door to significant advances in cancer treatment and beyond.

Please see terms and conditions
Disclosed herein are novel HDAC inhibitors. The HDAC inhibitors may be used in methods of treating cancer. The HDAC inhibitors may be used in methods of treating a neurological disorder.
1. A compound according to Formula (I):
Figure US20180258135A1-20180913-C00076
and stereoisomers and salts thereof;

wherein X is NH or O or a direct bond;
R1 is H, C1-10 alkyl, aryl, heteroaryl, or —NH—CHRaC(O)—OR4;
Ra is an amino acid side chain, H, C1-10 alkyl, C1-10 heteroalkyl, aryl, or heteroaryl;
R4 is H, C1-10 alkyl, heteroaryl or aryl;
R2 is SH, SeH, or C(O)NHOH, or the compound can form a disulfide or diselenide dimer at the R2 position;
R3 is H, C1-10 alkyl, heteroaryl, aryl, or —C(O)R5;
R5 is C1-10 alkyl, heteroaryl, aryl, or —CH(N(RN)2)(CR′R″ORO);
R′ is H or C1-10 alkyl, heteroaryl, or aryl;
R″ is H or C1-10 alkyl, heteroaryl, or aryl;
each RN is independently H, C1-10 alkyl, heteroaryl, or aryl;
RO is H, C1-10 alkyl, heteroaryl, or aryl;
Y is H, C1-10 alkyl, heteroaryl, aryl, or halogen;
n is an integer from 0 to 5;
wherein if X is a direct bond, then R1 is —NH—CHRaC(O)—OR4; and
wherein the dashed bond indicates the presence of an optional double bond.
2. A compound according to Formula (II):
Figure US20180258135A1-20180913-C00077
and stereoisomers and salts thereof;

wherein Z is S or Se;
X is NH or O or a direct bond;
R6 is H, C1-10 alkyl, heteroaryl, aryl, or —NH—CHRaC(O)—OR4;
Ra is an amino acid side chain, H, C1-10 alkyl, C1-10 heteroalkyl, aryl, or heteroaryl;
R4 is H, C1-10 alkyl, heteroaryl, or aryl;
R3 is H, C1-10 alkyl, heteroaryl, aryl, or —C(O)R5;
R5 is C1-10 alkyl, heteroaryl, aryl, or —CH(N(RN)2)(CR′R″ORO);
R′ is H, C1-10 alkyl, heteroryl, or aryl;
R″ is H, C1-10 alkyl, heteroaryl, or aryl;
each RN is independently H, C1-10 alkyl, heteroaryl, or aryl;
RO is H or C1-10 alkyl, heteroaryl, or aryl;
Y is H, C1-10 alkyl, heteroaryl, aryl, or halogen;
wherein if X is a direct bond, then R6 is —NH—CHRaC(O)—OR4;
n is an integer from 0 to 5; and
wherein the dashed bond indicates the presence of an optional double bond.
3. The compound according to claim 1 or claim 2, wherein X is a direct bond and R1 or R6 is —NH—CHRaC(O)—OR4.
4. The compound according to claim 1 or claim 2, wherein X is NH.
5. The compound according to claim 1 or claim 2, wherein X is O.
6. The compound according to any one of claims 1-3, wherien Ra is H, C1-10 alkyl, aryl, heteroaryl, or halogen.
7. The compound according to any one of claims 1-3, wherien Ra is an amino acid side chain.
8. The compound according to claim 7, wherein the amino acid is an aliphatic amino acid, hydroxyl- or sulfer- or selenium-containing amino acid, cyclic amino acid, aromatic amino acid, or basic amino acid.
9. The compound according to claim 7, wherein the amino acid is an aliphatic amino acid or a hydroxyl- or sulfer- or selenium-containing amino acid.
10. The compound according to claim 7, wherein the amino acid is glycine, alanine, isoleucine, leucine, serine, valine, or methionine.
11. The compound according to claim 7, wherein the amino acid is isoleucine, serine, valine, or methionine.
12. The compound according to any one of the preceding claims wherein, R1 is H.
13. The compound according to any one of claims 1-12, wherein R1 is C1-10 alkyl.
14. The compound according to claim 13, wherein R1 is C1-4 alkyl.
15. The compound according to any one of claims 1 and 3-9, wherein R2 is SH.
16. The compound according to any one of claims 1 and 3-14, wherein R2 is SeH.
17. The compound according to any one of claims 1 and 3-14, wherein the compound forms a disulfide dimer at the R2 position.
18. The compound according to any one of claims 1 and 3-14, wherein the compound forms a diselenide dimer at the R2 position.
19. The compound according to any of the preceding claims, wherein R3 is H.
20. The compound according to any one of claims 1-18, wherein R3 is —C(O)R5.
21. The compound according to claim 20, wherein R5 is —CH(N(RN)2)(CR′R″ORO).
22. The compound according to claim 21, wherein at least one RN is H.
23. The compound according to claim 21 or claim 22, wherein both RN are H.
24. The compound according to any one of claims 21-23, wherein RO is H.
25. The compound according to any one of claims 21-24, wherein one of R′ and R″ is H and the other is C1-10 alkyl.
26. The compound according to claim 25, wherein one of R′ and R″ is methyl.
27. The compound according to any one of claims 21-24, wherein both R′ and R″ are H.
28. The compound according to any one of claims 1-27, wherein R4 is H.
29. The compound according to any one of claims 1-27, wherein R4 is C1-10 alkyl.
30. The compound according to claim 29, wherein R4 is methyl or ethyl.
31. The compound according to any one of claims 1-30, wherein Y is H.
32. The compound according to any one of claims 2-31, wherein Z is S.
33. The compound according to any one of claims 2-31, wherein Z is Se.
34. The compound according to any one of claims 1-33, wherein the optional double bond is present.
35. The compound of claim 1 or 2, wherein the compound is selected from the group consisting of:
Figure US20180258135A1-20180913-C00078
Figure US20180258135A1-20180913-C00079
Figure US20180258135A1-20180913-C00080
Figure US20180258135A1-20180913-C00081
36. The compound of claim 1 or 2, wherein the compound is not at least one compound selected from the group consisting of:
Figure US20180258135A1-20180913-C00082
Figure US20180258135A1-20180913-C00083
Figure US20180258135A1-20180913-C00084
Figure US20180258135A1-20180913-C00085
Figure US20180258135A1-20180913-C00086
37. A pharmaceutical composition comprising a compound according to any one of the above claims and a pharmaceutically acceptable carrier.
38. A method of treating cancer comprising administering an effective amount of a compound according to any one of claims 1-36 to a subject in need thereof.
39. The method of claim 38, wherein the cancer is selected from colon, melanoma, ovarian, T cell lymphoma, and renal cancer.
40. A method of treating a subject with a neurological disorder, comprising administering an effect amount of a compound according to any one of claims 1-36 to a subject in need thereof.
41. The method of claim 40, wherein the neurological disorder is selected from the group consisting of dementia, memory deficit, memory dysfunction, memory loss, cognition defects, amyotrophic lateral sclerosis, Alzheimer’s Disease, Parkinson’s Disease, Huntington’s Disease, mood disorder, substance abuse, and schizophrenia.
42. The method claim 40, wherein the neurological disorder is selected from the group consisting of dementia, memory deficit, memory dysfunction, memory loss, cognition defects, and Alzheimer’s Disease.
43. The method of claim 41, wherein the mood disorder is selected from the group consisting of depression and bipolar disorder.
44. A method of enhancing memory and/or improving cognition comprising administering an effect amount of a compound according to any one of claims 1-36 to a subject in need thereof.
45. A method of inhibiting a HDAC in a subject in need thereof, the method comprising administering an effect amount of a compound according to any one of claims 1-36 to the subject.
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Title

Novel hdac inhibitors and methods of treatment using the same

Inventor(s)

Yi-Qiang Cheng, M. Mahmun Hossain, Douglas Steeber, Karyn Frick, Steven Clark, Joseph Ulicki

Assignee(s)

UWM Research Foundation Inc

Patent #

20180258135

Patent Date

September 13, 2018

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