Pyridazinones and their use in the treatment of cancer
Inventors
ARNÉR, Elias Set Jenö • STAFFORD, William Chester • COUSSENS, Nathan Patrick • LUCI, Diane Karen • Maloney, David Joseph • Simeonov, Anton • Jadhav, Ajit • Dexheimer, Thomas S.
Assignees
Elias Set Jeno Arner • US Department of Health and Human Services
Publication Number
US-11110089-B2
Publication Date
2021-09-07
Expiration Date
2036-08-05
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Abstract
There is provided compounds of formula (I) or pharmaceutically-acceptable salts thereof, wherein W, X, Y, Z, R1, R2 and R3 have meanings provided in the description, which compounds are useful in the treatment of cancers.
Core Innovation
The invention relates to novel pyridazinone compounds and compositions comprising the same for use in the treatment of cancer. These compounds specifically and potently inhibit cytosolic thioredoxin reductase without targeting glutathione reductase. This selective inhibition aims to provide an effective anticancer treatment with limited toxic side effects compared to broader antioxidant system inhibitors.
The problem addressed is the need for more effective and less toxic cancer treatments. Cancer cells produce excessive reactive oxygen species and survive by upregulating antioxidant defenses, mainly the glutathione and thioredoxin systems. Existing treatments that inhibit both systems risk severe toxicity to normal cells, which rely on either system for survival. The invention proposes selective inhibition of cytosolic thioredoxin reductase to overcome this challenge.
The inventors have found that novel pyridazinone compounds selectively inhibit cytosolic thioredoxin reductase over glutathione reductase, potentially making them effective against cancers with dysfunctional redox status while minimizing toxicity to normal cells. They may also be used as adjuvants with radiotherapies or chemotherapies, offering a new therapeutic mechanism that selectively impairs cancer cell antioxidant defense.
Claims Coverage
The patent contains one principal independent claim covering the chemical compound of formula I and a method claim for treating cancer with this compound, supported by additional related claims. The main inventive features are extracted as follows.
Compound of formula I with defined substituents
A chemical compound of formula I with specific definitions for W, X, Y, Z, R1, R2, R3, and other substituents, characterized by selective and potent inhibition of cytosolic thioredoxin reductase without targeting glutathione reductase.
Pharmaceutical use of the compound for cancer treatment
Use of the compound of formula I or pharmaceutically acceptable salts thereof for use as a pharmaceutical, particularly for the treatment of cancer, including specified cancer types such as pharyngeal squamous cell carcinoma, colorectal carcinoma, epidermoid (skin) carcinoma, and lung carcinoma.
Pharmaceutical composition comprising the compound
A pharmaceutical composition comprising the compound of formula I optionally combined with pharmaceutically acceptable adjuvants, diluents, or carriers for administration in cancer therapy.
Combination products and kits with other cancer therapeutics
Combination product comprising the compound of formula I with one or more other therapeutic agents useful in cancer treatment, and a kit-of-parts providing the compound alongside other cancer therapies for concomitant or sequential use.
Process for preparation of the compound
A process for preparing the compound of formula I involving specific chemical reactions, including coupling and ring closure steps using defined intermediates and reagents.
The claims collectively cover the novel pyridazinone compounds defined by formula I, their pharmaceutical use as selective thioredoxin reductase inhibitors in cancer treatment, pharmaceutical formulations, combination therapies with other anticancer agents, kits for combination therapy, and methods of synthesis.
Stated Advantages
Provide an efficient anticancer treatment that presents limited toxic side effects.
Achieve highly selective inhibition of cytosolic thioredoxin reductase without inhibiting glutathione reductase.
Potentially effective against cancers with dysfunctional redox status while minimizing toxic effects on normal cells.
Suitable as adjuvant therapy combined with radiotherapies or other chemotherapeutic approaches.
May be more efficacious, less toxic, longer acting, more potent, produce fewer side effects, more easily absorbed, or have better pharmacokinetic profiles than prior art compounds.
Documented Applications
Treatment of various cancers including soft tissue cancers, lung cancers, gastrointestinal cancers, genitourinary tract cancers, liver cancers, bone cancers, head and nervous system cancers, gynecological cancers, hematologic cancers, skin cancers, neuroblastomas, and others explicitly listed.
Treatment of specific cancer types such as pharyngeal squamous cell carcinoma, colorectal carcinoma, epidermoid (skin) carcinoma, lung carcinoma, pancreatic cancer, ovarian cancer, metastatic breast cancer, hepatobiliary cancer, gastric cancer, testicular cancer, head and neck squamous cell carcinoma, leukemia, lymphoma, and prostate cancer.
Use in combination with radiotherapy or other agents that increase reactive oxygen species to sensitize cancer cells to endogenous oxidative stress.
Therapeutic administration via various routes including oral, intravenous, subcutaneous, buccal, rectal, dermal, nasal, tracheal, bronchial, inhalation, and topical application.
Interested in licensing this patent?