Pharmaceutical combinations for the treatment of cancer
Inventors
Klinghoffer, Richard • DEY, Joyoti
Assignees
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Publication Number
US-12171744-B2
Publication Date
2024-12-24
Expiration Date
Abstract
The disclosure herein provides combination therapies for the treatment of cancers such as Leukemia, lymphoma and triple negative breast cancer. The disclosure provides combination therapies of CDK inhibitors, e.g., a CDK inhibitor represented by Formula (I): or a pharmaceutically acceptable salt thereof together with a BCL-2 inhibitor or proteasome inhibitor for the treatment of cancer.
Core Innovation
The invention relates to a method of treating a cancer selected from acute lymphocytic lymphoma (ALL), diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma, intravascular large B-cell lymphoma, follicular lymphoma, small lymphocytic lymphoma (SLL), mantle cell lymphoma, marginal zone B-cell lymphoma, extranodal marginal zone B-cell lymphoma, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma, primary central nervous system lymphoma, and triple negative breast cancer (TNBC) by administering a therapeutically effective amount of a CDK inhibitor represented by Formula I or a pharmaceutically acceptable salt thereof together with a therapeutically effective amount of a proteasome inhibitor.
The CDK inhibitor is defined by substituent selections including substituted phenyl for R1, hydroxy or OR8 with OR8 defining R2 and R3 as C1-C10-alkyl, substituted C1-C4-alkyl for R4, and C1-C4-alkyl for R9. The claimed treatment regimen includes combination-therapy administration, including concurrent co-administration or sequential administration within about 12 hours of each other.
The described rationale for combination dosing is based on synergy that permits further dose reduction, with documented results associating the combination with modulation of apoptosis and MCL-1/XIAP-related markers, including cPARP and CC3, and changes in pathways and effectors in cancer models including DLBCL and TNBC.
Claims Coverage
The independent claim provides two main inventive elements: a CDK inhibitor defined by Formula I and a proteasome inhibitor, administered to treat a specified list of cancers. The dependent refinements add specific cancer narrowing including TNBC, specific proteasome inhibitor selections, and administration timing relationships between the two inhibitor classes.
Formula I CDK inhibitor for treating selected cancers with proteasome inhibitor co-administration
A method of treating a selected cancer by administering a therapeutically effective amount of a CDK inhibitor represented by Formula I or a pharmaceutically acceptable salt thereof together with a therapeutically effective amount of a proteasome inhibitor.
Concurrent co-administration of CDK inhibitor and proteasome inhibitor
The method wherein the CDK inhibitor and the proteasome inhibitor are administered concurrently.
Sequential administration within about 12 hours
The method wherein the CDK inhibitor and a proteasome inhibitor are administered sequentially within about 12 hours of each other.
Proteasome inhibitor selection from enumerated group
The method wherein the proteasome inhibitor is selected from bortezomib, marizomib, ixazomib, disulfiram, epigallocatechin-3-gallate, salinosporamide A, carfilzomib, ONX 0912, CEP-18770, MLN9708, epoxomicin, MG132, or a pharmaceutically acceptable salt of any of these.
Triple negative breast cancer treatment indication
The method wherein the cancer is triple negative breast cancer (TNBC).
Specific R1 substituent definition within Formula I
The method characterized in that R1 is 2-chloro-4-trifluoromethylphenyl.
Overall claim coverage centers on combination treatment using a Formula I CDK inhibitor together with a therapeutically effective amount of a proteasome inhibitor for specified cancers, with refinements for concurrent versus sequential timing, explicit proteasome inhibitor alternatives, narrowing to TNBC, and specific Formula I substituent definition for R1.
Stated Advantages
Synergy that permits further dose reduction.
Documented Applications
Treatment of cancers including DLBCL and triple negative breast cancer (TNBC) using CDK inhibitor and proteasome inhibitor combination therapy, including in described cancer model contexts.
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