ATRA for modulating Pin1 activity and stability

Patent metadata

Field	Value
Publication number	US-9968579-B2
Application number	US-201515326979-A
Country	US
Kind code	B2
Filing date	Jul 16, 2015
Priority date	Jul 17, 2014
Publication date	May 15, 2018
Grant date	May 15, 2018

Abstract

The present disclosure describes how all-retinoic acid (ATRA) binds and inhibits Pin1 activity and induces degradation of the activated Pin1 monomer selectively in cancer cells. Identification of the binding mechanism of ATRA with Pin1 confirm ATRA binding specificity to Pin1 residues in the PPIase active site, thus demonstrating that drug-induced Pin1 ablation has potent anticancer activity, such as in acute promyelocytic leukemia (APL), by inducing PML-RARa degradation, as well as against other types of cancer and diseases that are associated with Pin1 overexpression, such as aggressive triple negative breast cancer, lupus, asthma, cocaine addiction, among others, due to their unique ability to simultaneously block numerous cancer-driving pathways, with relatively lower toxicity. The present disclosure also provides a rationale for developing sustained released ATRA-containing formulations. ATRA-containing formulations may be used in combinations with other existing therapies including chemotherapy or molecularly targeted drugs and other standard of care.

First claim

The invention claimed is:

1. A pharmaceutical composition comprising a retinoid, wherein said composition is formulated for long-term delivery of said retinoid after injection of said composition into a subject.

2. The pharmaceutical composition of claim 1 , wherein said composition is formulated as an injectable depot system, an injectable drug suspension, an injectable microsphere, or an injectable gel.

3. The pharmaceutical composition of claim 2 , wherein said injectable drug suspension is an oil-based suspension.

4. The pharmaceutical composition of claim 2 , wherein said composition is formulated for intravenous injection or intramuscular injection.

5. The pharmaceutical composition of claim 4 , wherein said composition is formulated as an injectable gel and for intramuscular injection.

6. The pharmaceutical composition of claim 5 , wherein said injectable gel remains in the muscle for at least 4-6 weeks after injection.

7. The pharmaceutical composition of claim 1 , wherein said composition is formulated to delay the metabolism of said retinoid.

8. The pharmaceutical composition of claim 7 , wherein said composition comprises one or more liposomes comprising said retinoid.

9. The pharmaceutical composition of claim 1 , further comprising a pharmaceutically acceptable excipient.

10. The pharmaceutical composition of claim 1 , wherein said retinoid is all-trans retinoic acid.

11. A method of treating a Pin1-related disorder in a subject in need thereof, comprising administering the composition of claim 1 to said subject.

12. The method of claim 11 , wherein said Pin1-related disorder is a cancer, an immune disorder, or cocaine addiction.

13. The method of claim 12 , wherein said cancer is selected from the group consisting of: acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroleukemia, chronic leukemia, chronic myelocytic leukemia, chronic lymphocytic leukemia, Hodgkin's disease, non-Hodgkin's disease, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, esophageal cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilm's tumor, cervical cancer, uterine cancer, testicular cancer, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodenroglioma, schwannoma, meningioma, melanoma, neuroblastoma, and retinoblastoma.

14. The method of claim 13 , wherein said cancer is breast cancer.

15. The method of claim 12 , wherein said immune disorder is asthma or lupus.

16. The method of claim 11 , wherein said subject is determined to have elevated levels of a Pin1 marker prior to said administration.

17. The method of claim 11 , further comprising administering a second therapeutic compound.

18. The method of claim 17 , wherein said second therapeutic compound is chemotherapeutic compound, a DAPK inhibitor, a SIRT1 inhibitor, a deacetylase inhibitor, a second Pin1 inhibitor, a Plk1 inhibitor, an anti-inflammatory compound, an antimicrobial compound, an antiviral compound, or any combination thereof.

19. The method of claim 17 , wherein said composition and said second therapeutic compound are administered separately or in a single formulation.

Assignees

• Beth Israel Deaconess Medical Ct Inc
• Beth Isreal Deaconess Medical Center Inc

Inventors

• Lu Kun Ping
• Zhou Xiao Zhen
• Wei Shuo

Classifications

• A61P37/02

  Immunomodulators · CPC title

• A61K9/5031

  obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide) · CPC title

• A61K31/353

  3,4-Dihydrobenzopyrans, e.g. chroman, catechin · CPC title

• A61K31/197

  the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid (carnitine A61K31/205) · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title