Non-invasive pet imaging of CDK4/6 activation in cancer
Inventors
Carlucci, Giuseppe • Reiner, Thomas
Assignees
New York University NYU • Memorial Sloan Kettering Cancer Center
Publication Number
US-12090157-B2
Publication Date
2024-09-17
Expiration Date
2041-04-30
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Abstract
Disclosed are compounds having the following structure: CDK-L-(X)n, where CDK is a CDK4/6 inhibitor group, L is a linking group, X is a radiolabel or hydrogen, n is 1, 2, 3, 4, or 5, and when there are a plurality of X groups, at least one X is a radiolabel. Also described are methods of making and using the compounds. The compounds may be used in PET imaging to quantify CDK4/6 expression in cancers and to treat cancer patients exhibiting tumors which express CDK4/6.
Core Innovation
The invention discloses compounds with the general structure CDK-L-(X)n, where CDK is a CDK4/6 inhibitor group, L is a linking group, and X is a radiolabel or hydrogen. At least one X is a radiolabel when n is greater than 1; preferred radiolabels include 18F, among others. These compounds are designed as non-invasive imaging agents, specifically for use in positron emission tomography (PET) to quantify CDK4/6 expression in cancers. The invention further includes pharmaceutical compositions comprising these compounds and methods of making and using them.
The problem addressed by this invention arises from the importance of CDK4/6 pathways in cancer development and therapeutic intervention. Dysregulation and overexpression of the cycD1-CDK4/6 axis are hallmarks of various cancers, including breast, head and neck, lung, melanoma, and glioblastoma. There is a need for precise, non-invasive methods to quantify CDK4/6 expression, monitor therapeutic response, guide patient selection for CDK4/6 inhibitor therapies, and detect or manage drug resistance.
This disclosure provides novel PET imaging agents, such as 18F-CDKi, which are radiolabeled derivatives of known CDK4/6 inhibitors like palbociclib. These compounds enable non-invasive imaging to assess CDK4/6 activity and expression in tumors. The invention includes methods for identifying individuals suitable for CDK4/6 inhibitor therapy, monitoring disease progression, and evaluating or adjusting therapy in resistant cases. The innovation is applicable to cancers characterized by CDK4/6 overexpression, including ER-positive, HER2-negative breast cancer and others as described herein.
Claims Coverage
There are four main inventive features covered by the independent claims of the patent.
Compound for non-invasive imaging with CDK4/6 inhibitor group and radiolabel
A compound having the structure CDK-L-(X)n, where: - CDK is a CDK4/6 inhibitor group of specified structure. - L is a linking group. - X is a radiolabel or hydrogen, with at least one X being a radiolabel when n > 1. - The radiolabel can be selected from 123I, 124I, 125I, 131I, 211At, 18F, and combinations thereof.
Pharmaceutical composition containing the inventive compound
A composition comprising the previously described compound for non-invasive imaging and a pharmaceutically acceptable carrier.
Method of treating CDK4/6 overexpression disease with the inventive compound
A method of treating a disease or disorder characterized by overexpression of CDK4/6 in an individual in need of treatment comprising administering an effective amount of the compound (CDK-L-(X)n) or a composition containing it.
Method for imaging tumors using the inventive compound via PET imaging
A method for imaging a tumor comprising: 1. Administering to an individual the CDK-L-(X)n compound or a composition containing it. 2. Subjecting the individual to PET imaging to obtain an image of the distribution of the compound in the tumor.
The inventive features collectively claim specific radiolabeled CDK4/6 inhibitor compounds, their pharmaceutical compositions, therapeutic use in CDK4/6 overexpression diseases (such as certain cancers), and their use as PET imaging agents for tumor localization and assessment.
Stated Advantages
Provides a non-invasive PET imaging agent for quantifying CDK4/6 expression in cancers.
Allows selection of patients suitable for CDK4/6 inhibitor therapies by visualizing accumulation in tumors.
Enables monitoring of cancer progression and assessment of therapeutic efficacy or resistance.
Improves accuracy in detecting functional CDK4/6 expression for more personalized treatment strategies.
Demonstrates high stability, high affinity, and rapid tumor uptake with fast washout from non-target tissues.
Documented Applications
Non-invasive PET imaging to quantify CDK4/6 expression in cancers, including ER-positive HER2-negative breast cancer.
Identification of individuals suitable for CDK4/6 inhibitor treatment by assessing tumor accumulation of the agent.
Monitoring the progression of cancer and the efficacy of cancer treatments involving CDK4/6 inhibitors.
Imaging and assessment in cancers such as breast cancer, head and neck cancer, non-small cell lung cancer, melanoma, and glioblastoma.
Treatment of diseases or disorders characterized by overexpression of CDK4/6 by administering the inventive compound or its compositions.
Evaluation and management of CDK4/6 inhibitor resistance by imaging agent uptake in tumors.
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