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A concise review on MDM2 inhibitors and recent progress in radiopharmaceutical development for imaging MDM2
Atchimnaidu Siriki1, Graham Ragland1, Janardhan Vasireddy1
1Department of Radiology, The University of Chicago, Chicago, IL 60637, United States.
Abstract:
Murine double minute 2 (MDM2, also known as human double minute 2 or HDM2) is a negative regulator of the tumor suppressor protein p53 and is overexpressed in many cancers. Over the past two decades, substantial progress has been made in developing inhibitors of the MDM2-p53 interaction, thereby allowing the p53 protein to exert antitumor effects through cell apoptosis and cycle arrest. While there are currently no FDA-approved MDM2 inhibitors available, several small molecule MDM2 inhibitors and a stapled peptide inhibitor of the MDM2-p53 interaction are in clinical development. Availability of these clinical candidates, representing a diverse array of chemical scaffolds that bind to the same p53 binding site on the MDM2 protein with low nanomolar inhibition potency (IC50), presents a significant opportunity for developing molecular imaging probes for MDM2 in parallel. This review summarizes the MDM2 inhibitors that have been evaluated in clinical trials, which could serve as starting leads for imaging probe development, and recent progress in developing radiotracers for MDM2 and for evaluating MDM2 expression levels in tumors noninvasively using the highly sensitive, molecular imaging techniques positron emission tomography (PET) or single-photon emission computed tomography (SPECT).
Insights
Developing molecular imaging probes for MDM2 is crucial for cancer diagnostics. This review highlights clinical-stage MDM2 inhibitors as potential leads for creating these probes, enabling noninvasive tumor assessment.
Area of Science:
- Oncology
- Molecular Biology
- Radiochemistry
Background:
- Murine double minute 2 (MDM2) is a key negative regulator of the tumor suppressor p53, frequently overexpressed in various cancers.
- Inhibitors targeting the MDM2-p53 interaction aim to restore p53's tumor-suppressive functions, including apoptosis and cell cycle arrest.
- Despite no FDA-approved MDM2 inhibitors, several candidates are in clinical development, showcasing diverse chemical scaffolds with high binding affinity.
Purpose of the Study:
- To review clinical-stage MDM2 inhibitors as potential starting points for developing molecular imaging probes.
- To summarize recent advancements in creating radiotracers for MDM2.
- To discuss the noninvasive evaluation of MDM2 expression levels in tumors using PET and SPECT.
Main Methods:
- Literature review of MDM2 inhibitors in clinical trials.
- Analysis of small molecule and peptide inhibitors targeting the MDM2-p53 interaction.
- Overview of radiotracer development for MDM2 imaging.
Main Results:
- Clinical candidates for MDM2 inhibition offer diverse scaffolds with low nanomolar potency.
- These inhibitors represent promising leads for the development of MDM2-specific imaging probes.
- Progress has been made in developing PET and SPECT radiotracers for MDM2.
Conclusions:
- Clinical MDM2 inhibitors provide a valuable foundation for developing novel molecular imaging agents.
- Noninvasive imaging of MDM2 expression can aid in cancer diagnosis and treatment monitoring.
- Further research in radiotracer development is essential for clinical translation.
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