Methods of treating radiation induced gastrointestinal syndrome (RIGS) and related disease states using YEL002/BCN057
Inventors
Saha, Subhrajit • NORRIS, ANDREW J.
Assignees
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Publication Number
US-11364231-B2
Publication Date
2022-06-21
Expiration Date
Abstract
The present disclosure is directed to method of treatment for treating or ameliorating various conditions caused by radiation exposure such as RIGS, enteritis, oral mucositis, mucositis, and proctitis by the administration of a compound Yel002/BCN057 or an analog thereof.
Core Innovation
The invention relates to a method of treating radiation or chemotherapy induced damage to epithelial cells in a subject in need thereof by administering a therapeutically effective amount of a compound of Formula I. The compound family includes small-molecule YEL002/BCN057, represented by Formula IA/Formula I with variable substituents R1–R3, and related analogs.
BCN057 is disclosed as a WNT/β-catenin pathway agonist through TCF/LEF reporter activity and increased nuclear β-catenin localization. The disclosure states that this agonist activity rescues intestinal stem cells, including Lgr5+ intestinal stem cells, and promotes intestinal crypt-villus repair in irradiated models.
The treated epithelial cell damage is identified as one or more of radiation-induced gastrointestinal syndrome (RIGS), chemotherapy-induced gastrointestinal syndrome, radiation-induced mucositis, chemotherapy-induced mucositis, radiation-induced oral mucositis, chemotherapy-induced oral mucositis, radiation-induced proctitis, chemotherapy-induced proctitis, chemotherapy-induced enteritis, or radiation-induced enteritis. The disclosure also mentions mitigation of radiation injuries, including hematopoietic syndrome, improved survival when administered after lethal abdominal irradiation, reduction of serum FITC-dextran, and a lack of radio-protective effect in malignant or tumor organoids and tumor tissue.
Claims Coverage
The document provides one independent claim covering treatment of specified epithelial cell damage using a therapeutically effective amount of a compound of Formula I. The independent claim is refined by dependent claims that add post-radiation timing constraints, narrower compound selection variants, and the context of radiation therapy.
Treating epithelial cell damage from radiation or chemotherapy with a Formula I compound
A method of treating radiation or chemotherapy induced damage to epithelial cells in a subject in need thereof by administering a therapeutically effective amount of a compound of Formula I, where R1 and R2 are independently selected from the group consisting of hydrogen, amino, amide, F, Cl, Br, I, nitro, alkoxy, hydroxyl, thiol, alkylthio, acyl carboxylic acid, ester, sulfonyl, sulfonamide, —SO4H, optionally substituted C1-C20 alkyl, optionally substituted C1-C20 alkenyl, optionally substituted C1-C20 alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, and optionally substituted phenyl, and where R3 is optionally substituted C1-C20 alkyl, optionally substituted C1-C20 alkenyl, optionally substituted C1-C20 alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl, optionally substituted heteroaryl, or optionally substituted phenyl; and wherein the radiation or chemotherapy induced damage to epithelial cells is identified as one or more of radiation-induced gastrointestinal syndrome (RIGS), chemotherapy-induced gastrointestinal syndrome, radiation-induced mucositis, chemotherapy-induced mucositis, radiation-induced oral mucositis, chemotherapy-induced oral mucositis, radiation-induced proctitis, chemotherapy-induced proctitis, chemotherapy-induced enteritis or radiation-induced enteritis.
Administering within 48 hours after radiation exposure
The method where the compound is administered to the subject within 48 hours after radiation exposure.
Administering after 24 hours of radiation exposure
The method where the compound is administered to the subject after 24 hours of radiation exposure.
Using a Formula I analog selected from Formula IE, IF, IG, and IH
The method where the analog is selected from the group consisting of Formula IE, IF, IG, and IH.
Using the Formula IA compound
The method characterized by using a compound corresponding to Formula IA.
Treating a subject receiving radiation therapy
The method wherein the subject receives radiation therapy.
Overall, the claim coverage is centered on treating radiation- or chemotherapy-induced epithelial cell damage associated with RIGS and gastrointestinal mucositis, proctitis, and enteritis by administering a therapeutically effective Formula I compound, with dependent claims further specifying post-radiation timing, Formula IA or selected Formula I analogs, and radiation therapy as the exposure context.
Stated Advantages
Improved survival when administered after lethal abdominal irradiation.
Reduction of serum FITC-dextran, described as restored epithelial integrity.
Lack of radio-protective effect in malignant or tumor organoids and tumor tissue.
Documented Applications
Mitigation or treatment of radiation-induced gastrointestinal syndrome (RIGS) and related radiation injuries, including radiation-induced enteritis, radiation-induced oral/GI mucositis, and radiation-induced proctitis.
Mitigation or treatment of chemotherapy-induced gastrointestinal syndrome and related chemotherapy-induced gastrointestinal mucositis, proctitis, and enteritis.
Use in irradiated models and human colon organoids for intestinal crypt-villus repair and rescue of intestinal stem cells.
Use described in ex vivo crypt organoid model and tumor organoid/tumor tissue contexts, where a lack of radio-protective effect is stated for malignant or tumor organoids/tumor tissue.
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