Uses of indolinone compounds
Inventors
Lannutti, Brian • Jessen, Katayoun • Breitmeyer, James Bradley
Assignees
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Publication Number
US-12161626-B2
Publication Date
2024-12-10
Expiration Date
Abstract
Methods and compositions for treating acute myeloid leukemia and diffuse large B cell lymphoma using combinations of venetoclax and indolinone derivatives are provided.
Core Innovation
The disclosure relates to a pharmaceutical composition and combination therapy using at least one therapeutic agent together with a compound having Formula (I) or a defined structure, including stereoisomers, pharmaceutically acceptable salts, and solvates. The indolinone derivative scaffold includes specific examples such as TK216, and the combination therapy context is explicitly tied to apoptosis induction and inhibition of proliferation in selected cell types derived from acute myeloid leukemia or diffuse large B cell lymphoma.
The chemical embodiments include substituted indolinone/aryl-containing structures, and the disclosure describes physical forms including amorphous form, crystalline polymorphs, and solvates. The combination therapy is described with agents selected from rituximab, bendamustine, ibrutinib, idelalisib, birabresib, bimiralisib, selinexor, and ACP196, together with a Formula (I) indolinone compound or a stereoisomer, pharmaceutically acceptable salt, or solvate thereof.
Biological support in the disclosure discusses apoptosis-related markers such as caspase-3, xenograft tumor growth inhibition, and combination synergism with additional specified agents. The disclosure also frames a mechanistic narrative targeting EWS-FLI1/ETS transcription factor activity, and it reports preclinical and clinical linkage narrative involving acute myeloid leukemia and diffuse large B cell lymphoma models.
Claims Coverage
The independent claims are directed to a pharmaceutical composition for combination therapy and a method for inducing apoptosis using a defined structural compound together with at least one specified therapeutic agent. Across the independent claims, two principal inventive features recur: the defined combination of a listed therapeutic agent with a compound defined by Formula (I) or a depicted structure, including stereoisomers, pharmaceutically acceptable salts, or solvates, and the apoptosis-related objective in specified cell types for the method claim.
Combination pharmaceutical composition with selected therapeutic agents and Formula (I) compound
A pharmaceutical composition for combination therapy comprising at least one therapeutic agent selected from rituximab, bendamustine, ibrutinib, idelalisib, birabresib, bimiralisib, selinexor, and ACP196; and a compound having a structure of Formula (I) or a depicted structure, or a stereoisomer, a pharmaceutically acceptable salt, ester, or solvate thereof.
Apoptosis induction in leukemia and lymphoma cells using the combination
A method for inducing apoptosis in a cell comprising a myeloblast produced in acute myeloid leukemia or a lymphocyte produced in diffuse large B cell lymphoma, comprising contacting the cell with an effective amount of a combination of at least one therapeutic agent selected from rituximab, bendamustine, ibrutinib, idelalisib, birabresib, bimiralisib, selinexor, and ACP196; and a compound having a structure of Formula (I) or a depicted structure, or a stereoisomer, a pharmaceutically acceptable salt, ester, or solvate thereof.
Overall claim coverage centers on combination therapy that pairs one or more of the explicitly listed therapeutic agents with a compound defined by Formula (I) or a depicted chemical structure, including stereoisomers, pharmaceutically acceptable salts, esters, or solvates, and on inducing apoptosis in AML myeloblasts or DLBCL lymphocytes by contacting those cells with an effective amount of that combination.
Stated Advantages
Induces apoptosis/aptosis and inhibits proliferation.
Combination synergism is presented with additional specified agents.
Xenograft tumor growth inhibition is presented.
Apoptosis and proliferation effects are discussed in acute myeloid leukemia and diffuse large B cell lymphoma models.
Documented Applications
Treating acute myeloid leukemia (AML), including myeloblasts produced in acute myeloid leukemia, using combination therapy including a venetoclax combination and other listed agents together with an indolinone derivative of Formula (I).
Treating diffuse large B-cell lymphoma (DLBCL), including lymphocytes produced in diffuse large B cell lymphoma, using combination therapy including a venetoclax combination and other listed agents together with an indolinone derivative of Formula (I).
Combination therapy synergy is reported in cell-line and xenograft contexts via referenced figures.
Combination therapy using a pharmaceutical composition comprising at least one therapeutic agent selected from the listed group together with a compound having the depicted structure, including stereoisomers, pharmaceutically acceptable salts, esters, or solvates.
Inducing apoptosis in a cell comprising a myeloblast produced in acute myeloid leukemia or a lymphocyte produced in diffuse large B cell lymphoma by contacting the cell with an effective amount of the specified combination.
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