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Identification and characterization of the first small molecule inhibitor of MDMX
Damon Reed1, Ying Shen, Anang A Shelat
1Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Abstract:
The p53 pathway is disrupted in virtually every human tumor. In approximately 50% of human cancers, the p53 gene is mutated, and in the remaining cancers, the pathway is dysregulated by genetic lesions in other genes that modulate the p53 pathway. One common mechanism for inactivation of the p53 pathway in tumors that express wild-type p53 is increased expression of MDM2 or MDMX. MDM2 and MDMX bind p53 and inhibit its function by distinct nonredundant mechanisms. Small molecule inhibitors and small peptides have been developed that bind MDM2 in the p53-binding pocket and displace the p53 protein, leading to p53-mediated cell cycle exit and apoptosis. To date, peptide inhibitors of MDMX have been developed, but no small molecule inhibitors have been reported. We have developed biochemical and cell-based assays for high throughput screening of chemical libraries to identify MDMX inhibitors and identified the first MDMX inhibitor SJ-172550. This compound binds reversibly to MDMX and effectively kills retinoblastoma cells in which the expression of MDMX is amplified. The effect of SJ-172550 is additive when combined with an MDM2 inhibitor. Results from a series of biochemical and structural modeling studies suggest that SJ-172550 binds the p53-binding pocket of MDMX, thereby displacing p53. This lead compound is a useful chemical scaffold for further optimization of MDMX inhibitors that may eventually be used to treat pediatric cancers and various adult tumors that overexpress MDMX or have similar genetic lesions. When combined with selective MDM2 inhibitors, SJ-172550 may also be useful for treating tumors that express wild-type p53.
Insights
Researchers identified the first small molecule inhibitor, SJ-172550, targeting MDM2-amplified and X (MDMX) protein, a key player in human cancers. This discovery offers a new therapeutic strategy for various tumors, including pediatric cancers, by restoring p53 tumor suppressor activity.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- The p53 pathway is crucial for tumor suppression and is frequently disrupted in human cancers through gene mutation or pathway dysregulation.
- In tumors with wild-type p53, increased MDM2 or MDMX expression inactivates the p53 pathway by inhibiting p53 function.
- While MDM2 inhibitors exist, effective small molecule inhibitors for MDMX have been lacking.
Purpose of the Study:
- To identify the first small molecule inhibitor targeting MDMX.
- To evaluate the efficacy of MDMX inhibitors in cancer treatment, particularly in combination with MDM2 inhibitors.
Main Methods:
- Development of biochemical and cell-based high-throughput screening assays for MDMX inhibitors.
- Identification and characterization of the first MDMX inhibitor, SJ-172550.
- Biochemical and structural modeling studies to elucidate the binding mechanism of SJ-172550.
Main Results:
- The first small molecule MDMX inhibitor, SJ-172550, was identified.
- SJ-172550 binds reversibly to MDMX, displacing p53 and killing retinoblastoma cells with amplified MDMX.
- SJ-172550's effect is additive with MDM2 inhibitors, suggesting combined therapeutic potential.
Conclusions:
- SJ-172550 represents a novel chemical scaffold for developing MDMX inhibitors.
- This compound holds promise for treating pediatric cancers and adult tumors overexpressing MDMX.
- Combination therapy with MDM2 inhibitors may benefit tumors with wild-type p53.
