Development of potential antidotes for arsenicals
Inventors
Suto, Mark J. • Mathew, Bini • Augelli-Szafran, Corinne E. • Yatchang, Marina Fosso • Athar, Mohammad • Agarwal, Anupam • Srivastava, Ritesh Kumar • Muzaffar, Suhail • Khan, Jasim
Assignees
UAB Research Foundation • Southern Research Institute • US Department of Veterans Affairs
Publication Number
US-12215108-B2
Publication Date
2025-02-04
Expiration Date
2043-01-10
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Abstract
The present disclosure is concerned with purine diamine compounds for the treatment of conditions associated with BRD4, RIP3K, and/or IL6 signaling dysfunction such as, for example, cancer (e.g., lung cancer, skin cancer, bladder cancer, kidney cancer, liver cancer), arsenicosis, arsenic poisoning, inflammation, skin lesions, dysfunction of systemic organs, and skin blisters. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.
Core Innovation
The invention relates to purine diamine compounds useful in the prevention and treatment of conditions associated with signaling dysfunction of BRD4, RIP3K, and/or IL6. The disclosed compounds, compositions, and methods address diseases such as cancer (including lung, skin, bladder, kidney, and liver cancers), arsenicosis, arsenic poisoning, inflammation, skin lesions, dysfunction of systemic organs, and skin blisters. The compounds have specific structural formulas with defined substituents and pharmaceutical compositions comprising these compounds are also disclosed.
The problem addressed is the widespread risk of adverse health effects from arsenic exposure, primarily through drinking water, food, soil, and air. Inorganic arsenic, especially from well water, is acutely toxic and causes cancer, vascular, neurological, and other systemic effects. Despite the prevalence of arsenic exposure and its health impacts, effective methods of treating arsenic poisoning have remained elusive. There remains a need for compounds and compositions for treating arsenic-related conditions and methods of making and using such compounds.
Claims Coverage
The patent includes one independent claim focused on the compound's chemical structure and its pharmaceutical composition, covering the compound and its use in treatment.
Compound having a specific purine diamine structure
A compound characterized by a detailed purine diamine chemical structure with multiple variable substituents (R1a to R17, Cy1, Cy2, Z, Q, R20, R21), providing specificity in chemical functionality for biological activity.
Pharmaceutical composition comprising the compound
A pharmaceutical composition including an effective amount of a disclosed compound and a pharmaceutically acceptable carrier, formulated for therapeutic use.
Method of treating conditions associated with BRD4, RIP3K, and/or IL6 signaling dysfunction
Administering an effective amount of a disclosed purine diamine compound to a subject in need thereof to treat conditions such as cancer, arsenicosis, arsenic poisoning, inflammation, skin lesions, dysfunction of systemic organs, and skin blisters.
Method of modifying BRD4, RIP3K, and/or IL6 signaling
Administering an effective amount of a disclosed compound to modify signaling pathways of BRD4, RIP3K, and/or IL6 in a subject or in a cell to achieve therapeutic or prophylactic effects.
Kit comprising the disclosed compound and treatment components
A kit including the compound, optionally combined with an agent associated with treatment of BRD4, RIP3K, and/or IL6 signaling dysfunction, and instructions for administration and treatment.
The claims focus on the novel chemical structure of purine diamine compounds, pharmaceutical compositions containing them, methods of treating and modifying relevant signaling pathways to address arsenic-related and cancer conditions, and kits for their therapeutic use.
Stated Advantages
The compounds alleviate cutaneous injury, pulmonary, and renal toxicity as countermeasures against chemical vesicant exposure.
Compound no. 11 effectively inhibits BRD4 and RIP3K activation, reducing inflammation and tissue damage in arsenical-induced skin injury models.
Compound no. 11 shows significant dose-dependent reduction of BRD4 expression, histone acetylation marks, and transcription of inflammatory and tissue damage-associated genes.
Compound no. 11 provides superior or comparable protection against arsenical-induced skin injury relative to other known BRD4 inhibitors.
The compounds target multiple pathways including epigenetic, inflammatory, and necrosis-related signaling for comprehensive treatment effects.
Documented Applications
Treatment of conditions associated with BRD4, RIP3K, and/or IL6 signaling dysfunction such as cancer (lung, skin, bladder, kidney, liver), arsenicosis, arsenic poisoning, inflammation, skin lesions, dysfunction of systemic organs, and skin blisters.
Treatment or prevention of health effects caused by arsenical exposure via ingestion, inhalation, or dermal absorption, including acute lung injury, acute kidney injury, chronic kidney disease, liver damage, neurological alterations, and immune dysregulation.
Use of compounds as antidotes and therapeutic agents for chemical vesicant injury caused by arsenicals such as PAO and lewisite.
Pharmaceutical compositions and therapeutic methods for modifying BRD4, RIP3K, and IL6 signaling in subjects or cells for managing associated diseases.
Kits combining the disclosed compounds with other therapeutic agents and instructions for treating related signaling dysfunctions and diseases.
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