Enhanced ATRA-related compounds for the treatment of proliferative diseases, autoimmune diseases, and addiction conditions

Patent metadata

Field	Value
Publication number	US-10548864-B2
Application number	US-201615557731-A
Country	US
Kind code	B2
Filing date	Mar 10, 2016
Priority date	Mar 12, 2015
Publication date	Feb 4, 2020
Grant date	Feb 4, 2020

Abstract

The invention features all-trans retinoic acid (ATRA)-related compounds capable of associating with Pin1 and methods of treating a proliferative disorder characterized by elevated Pin1 marker levels, Pin1 degradation, and/or reduced Pin1 Ser71 phosphorylation in a subject by administering an ATRA-related compound. The invention also features methods of treating proliferative disorders, autoimmune diseases, and addiction conditions (e.g., diseases, disorders, and conditions characterized by elevated Pin1 marker levels) by administering an ATRA-related compound in combination with another therapeutic compound.

First claim

What is claimed is:

1. A method of treating a cancer in a subject with elevated levels of a Pin1 marker, said method comprising administering an all-trans retinoic acid (ATRA)-related compound to said subject in an amount sufficient to treat said subject, wherein said ATRA-related compound has the formula

wherein W is an optionally substituted triazole, and
R 1 , R 2 , and R 3 are independently selected from the group consisting of a halogen atom, a carboxylic acid, an alcohol, an ester, an aldehyde, a carbonyl, an acyl halide, a carbonate, an acetal, a phosphate, a thiol, a sulfoxide, a sulfinic acid, a sulfonic acid, a thial, a sulfate, a sulfonyl, an amide, an azido, a nitro, a cyano, an isocyano, an acyloxy, an amino, a carbamoyl, a sulfonamide, an optionally substituted C1-C10 alkyl, an optionally substituted C2-C10 alkenyl, an optionally substituted C2-C10 alkynyl, an optionally substituted C1-C10 alkoxy, an optionally substituted C6-C10 aryloxy, an optionally substituted C3-C8 cycloalkyl, an optionally substituted C3-C8 cycloalkoxy, an optionally substituted C6-C10 aryl, an optionally substituted C6-10 aryl-C1-C10 alkoxy, an optionally substituted C3-C8 heterocyclyl, an optionally substituted C3-C8 heterocycloalkyl, an optionally substituted C4-C8 heterocycloalkenyl, or an optionally substituted C6-C10 heteroaryl group.

2. The method of claim 1 , wherein, prior to said administering, the method comprises determining the level of said Pin1 marker in a sample from said subject.

3. The method of claim 1 , wherein said subject has been previously treated with an ATRA-related compound and exhibits Pin1 degradation.

4. The method of claim 1 , wherein, after said administering, said method further comprises determining whether said subject has Pin1 degradation.

5. The method of claim 1 , wherein one or more of R 1 , R 2 , and R 3 are methyl groups.

6. The method of claim 1 , wherein the ATRA-related compound has the formula of

7. The method of claim 1 , wherein the ATRA-related compound is selected from the group consisting of

8. The method of claim 1 , wherein said Pin1 marker is reduced Ser71 phosphorylation of Pin1 or overexpression of PML-RARα.

9. The method of claim 1 , further comprising determining Pin1 marker levels in a sample from said subject after said administration of said compound.

10. The method of claim 9 , wherein said sample is selected from the group consisting of tumor samples, blood, urine, biopsies, lymph, saliva, phlegm, and pus.

11. The method of claim 1 , wherein said elevated Pin1 marker level is due to an inherited trait or a somatic mutation.

12. The method of claim 1 , further comprising administering a second therapeutic compound to the subject.

13. The method of claim 12 , wherein:
(a) said second therapeutic compound is an anti-proliferative compound, an anti-inflammatory compound, an anti-microbial compound, or an anti-viral compound;
(b) said second therapeutic compound is administered at a low dosage or at a different time;
(c) said second therapeutic compound is formulated as a liposomal formulation or a controlled release formulation; or
(d) said ATRA-related compound and said second therapeutic compound are formulated together.

14. The method of claim 13 , wherein:
(a) said anti-proliferative compound is selected from the group consisting of MK-2206, ON013105, RTA402, BI 2536, Sorafenib, and ISIS-STAT3Rx;
(b) said anti-proliferative compound is selected from the group consisting of microtubule inhibitors, topoisomerase inhibitors, platins, alkylating agents, and anti-metabolites;
(c) said anti-proliferative compound is selected from the group consisting of paclitaxel, gemcitabine, doxorubicin, vinblastine, etoposide, 5-fluorouracil, carboplatin, altretamine, aminoglutethimide, amsacrine, anastrozole, azacitidine, bleomycin, busulfan, carmustine, chlorambucil, 2-chlorodeoxyadenosine, cisplatin, colchicine, cyclophosphamide, cytarabine, cytoxan, dacarbazine, dactinomycin, daunorubicin, docetaxel, estramustine phosphate, floxuridine, fludarabine, gentuzumab, hexamethylmelamine, hydroxyurea, ifosfamide, imatinib, interferon, irinotecan, lomustine, mechlorethamine, melphalen, 6-mercaptopurine, methotrexate, mitomycin, mitotane, mitoxantrone, pentostatin, procarbazine, rituximab, streptozocin, tamoxifen, temozolomide, teniposide, 6-thioguanine, topotecan, trastuzumab, vincristine, vindesine, and vinorelbine;
(d) said anti-inflammatory compound is selected from the group consisting of corticosteroids, NSAIDs, COX-2 inhibitors, biologics, small molecule immunomodulators, non-steroidal immunophilin-dependent immunosuppressants, 5-amino salicylic acids, and DMARDs;
(e) said anti-inflammatory compound is selected from the group consisting of naproxen sodium, diclofenac sodium, diclofenac potassium, aspirin, sulindac, diflunisal, piroxicam, indomethacin, ibuprofen, nabumetone, choline magnesium trisalicylate, sodium salicylate, salicylsalicylic acid (salsalate), fenoprofen, flurbiprofen, ketoprofen, meclofenamate sodium, meloxicam, oxaprozin, sulindac, tolmetin, rofecoxib, celecoxib, valdecoxib, lumiracoxib, inflixamab, adelimumab, etanercept, CDP-870, rituximab, atlizumab, VX 702, SCIO 469, doramapimod, RO 30201195, SCIO 323, DPC 333, pranalcasan, mycophenolate, merimepodib, cyclosporine, tacrolimus, pimecrolimus, ISAtx247, mesalamine, sulfasalazine, balsalazide disodium, olsalazine sodium, methotrexate, leflunomide, minocycline, auranofin, gold sodium thiomalate, aurothioglucose, azathioprine, hydroxychloroquine sulfate, and penicillamine;
(f) said anti-inflammatory compound is selected from the group consisting of algestone, 6-alpha-fluoroprednisolone, 6-alpha-methylprednisolone, 6-alpha-methylprednisolone 21-acetate, 6-alpha-methylprednisolone 21-hemisuccinate sodium salt, 6-alpha,9-alpha-difluoroprednisolone 21-acetate 17-butyrate, amcinafal, beclomethasone, beclomethasone dipropionate, beclomethasone dipropionate monohydrate, 6-beta-hydroxycortisol, betamethasone, betamethasone-17-valerate, budesonide, clobetasol, clobetasol propionate, clobetasone, clocortolone, clocortolone pivalate, cortisone, cortisone acetate, cortodoxone, deflazacort, 21-deoxycortisol, deprodone, descinolone, desonide, desoximethasone, dexamethasone, dexamethasone-21-acetate, dichlorisone, diflorasone, diflorasone diacetate, diflucortolone, doxibetasol, fludrocortisone, flumethasone, flumethasone pivalate, flumoxonide, flunisolide, fluocinonide, fluocinolone acetonide, 9-fluorocortisone, fluorohydroxyandrostenedione, fluorometholone, fluorometholone acetate, fluoxymesterone, flupredidene, fluprednisolone, flurandrenolide, formocortal, halcinonide, halometasone, halopredone, hyrcanoside, hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone cypionate, hydrocortisone sodium phosphate, hydrocortisone sodium succinate, hydrocortisone probutate, hydrocortisone valerate, 6-hydroxydexamethasone, isoflupredone, isoflupredone acetate, isoprednidene, meclorisone, methylprednisolone, methylprednisolone acetate, methylprednisolone sodium succinate, paramethasone, paramethasone acetate, prednisolone, prednisolone acetate, prednisolone metasulphobenzoate, prednisolone sodium phosphate, prednisolone tebutate, predniso

Assignees

• Beth Israel Deaconess Medical Ct Inc
• Pinteon Therapeutics Inc

Inventors

• Lu Kun Ping
• Zhou Xiao Zhen
• Wei Shuo
• Sun Lijun
• Hall Michelle Lynn

Classifications

• A61K31/42

  Oxazoles · CPC title

• A61K31/5375

  1,4-Oxazines, e.g. morpholine · CPC title

• A61K31/4406

  only substituted in position 3, e.g. zimeldine (nicotinic acid A61K31/455) · CPC title

• A61K31/4245

  Oxadiazoles · CPC title

• A61K45/06

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