Combination comprising HDAC inhibitor and CD137 agonist for cancer therapy
Inventors
Assignees
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Publication Number
US-12285410-B2
Publication Date
2025-04-29
Expiration Date
Abstract
The invention relates to medical uses of an HDAC inhibitor of the below general formula I, wherein R1 to R7 are as described herein, or a salt or solvate thereof in combination with a CD137 agonist for the treatment of cancer.
Core Innovation
The invention relates to a method for the treatment of cancer by administering to a subject in need thereof an effective amount of an HDAC inhibitor of formula I, or a salt or solvate thereof, in combination with a CD137 agonist. The method is grounded in the structural definition of formula I, including the selection of substituents for R1, R2, R3, R4, R5 and R6, and the associated allowed groups Aa1, Hh1, Ha1, Ha2, Ha3, Ha4, Ah1, U, T1 to T5, Het1 to Het4, and V.
Formula I includes R6 as -T1-Q1, in which T1 is a bond or 1-4C-alkylene and Q1 is selected to be Aa1, Hh1, Ha1, Ha2, Ha3, Ha4 or Ah1, or Q1 is unsubstituted as an additional allowed case. For substituted embodiments, Q1 is not substituted by R61 and/or R62, while R61 is limited to enumerated groups such as halogen, trifluoromethyl, cyano, hydroxyl, 1-4C-alkyl, phenyl-1-4C-alkyl, fluorine-substituted alkoxy variants, sulphonamide and carbonylamino, and related substituents.
The combination is positioned for cancer therapy in the context of CD137 signaling in activated T and NK cells, and HDAC inhibitor activity involving cell-cycle arrest and apoptosis through changes in gene expression. The disclosure further identifies specific embodiments using 4SC-202, including the tosylate salt, and combines it with a CD137 agonist selected from enumerated agents including anti-CD137 antibody and named agonists, with cancer indications including triple-negative breast cancer and microsatellite-stable gastroesophageal or colorectal cancer.
Claims Coverage
The provided claim coverage centers on one independent claim requiring an HDAC inhibitor of formula I (or salt/solvate) combined with a CD137 agonist for treating cancer, with the inventive features defined by the formula I structure and the combined administration.
Combined cancer treatment with formula I HDAC inhibitor and CD137 agonist
Administering an effective amount of an HDAC inhibitor of formula I or a salt or solvate thereof in combination with a CD137 agonist to a subject in need thereof.
Formula I HDAC inhibitor structural definition
The HDAC inhibitor is defined by formula I with R1, R2, R3, R4, R5 and R6 substituent options, including R6 as -T1-Q1 and permitted groups Aa1, Hh1, Ha1, Ha2, Ha3, Ha4, Ah1, U, T1 to T5, Het1 to Het4, and V.
Terminal radical selection with Q1 substitution constraint and defined R61
Q1 is selected from Aa1, Hh1, Ha1, Ha2, Ha3, Ha4 or Ah1, or is unsubstituted, and substituted variants do not permit substitution by R61 and/or R62; R61 is restricted to enumerated substituents including alkyl, aryl-alkyl, alkoxy, fluorinated alkoxy, hydroxyl, trifluoromethyl, cyano, halogen, sulphonamide, carbonylamino, and related nitrogen-containing linker or heterocycle fragments.
CD137 agonist selection for combination therapy
The CD137 agonist component is selected from enumerated agents, including anti-CD137 antibody and named agonists.
Coverage is centered on a single independent method claim for cancer treatment by combined administration of a formula I HDAC inhibitor (or salt/solvate) with a CD137 agonist, with structural restrictions on the HDAC inhibitor and embodiments specifying particular CD137 agonists and cancer indications.
Stated Advantages
The combination is positioned for cancer therapy.
HDAC inhibitor activity involves cell-cycle arrest and apoptosis through changes in gene expression.
Stronger significant tumor control for the combined 4SC-202 plus a CD137 agonist versus either monotherapy.
Documented Applications
Treatment of cancer.
Triple-negative breast cancer.
Microsatellite-stable gastroesophageal cancer.
Microsatellite-stable colorectal cancer.
In vivo anti-tumor evaluation in a Colon 38 (C38) tumor model using 4SC-202, including 4SC-202 tosylate, combined with a CD137 agonist, with reported regression/remission proportions.
Treatment of cancer by administering an HDAC inhibitor of formula I, or a salt or solvate, in combination with a CD137 agonist to a subject in need thereof.
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