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Updated: May 20, 2025
Method for Identifying Small Molecule Inhibitors of the Protein-protein Interaction Between HCN1 and TRIP8b
Published on: November 11, 2016
Identification of small molecule inhibitors of PPM1D using an integrated drug discovery platform
Subrata Shaw1,2, Wei Jiang1,2, Jason Rush1,2
1Broad Institute of MIT and Harvard University, Cambridge, MA, USA.
Abstract:
PPM1D is a serine/threonine phosphatase recurrently activated in cancer, regulates the DNA damage response (DDR), and suppresses p53. Though PPM1D inhibition impairs tumor growth in cancer models and is the subject of multiple drug discovery efforts, no PPM1D inhibitors with clinical potential have been identified. We screened 600,000 compounds in a displacement assay and generated a hit series with nanomolar activity. We optimized our leads using internally developed assays to interrogate PPM1D, p53, and the DDR and defined important structure-activity relationships. Using an in vivo bioluminescent readout of p53 activation, we compared different DDR and p53 modulators and showed that despite having a distinct chemical structure, our lead compound had comparable in vivo activity to established PPM1D inhibitors. Our approach yielded multiple allosteric inhibitors of PPM1D, deepened our understanding of PPM1D as a drug target, and is highly amenable to studying other modulators of the DDR and p53.
Insights
Researchers identified novel allosteric inhibitors for PPM1D, a key regulator of the DNA damage response (DDR) and p53, offering new therapeutic potential for cancer treatment.
Area of Science:
- Biochemistry and Molecular Biology
- Cancer Biology
- Drug Discovery
Background:
- The serine/threonine phosphatase PPM1D is frequently activated in cancer, playing a critical role in regulating the DNA damage response (DDR) and suppressing the tumor suppressor p53.
- While PPM1D inhibition shows promise in preclinical cancer models, the lack of clinically viable PPM1D inhibitors has hindered therapeutic development.
Purpose of the Study:
- To identify and characterize novel inhibitors of PPM1D with potential clinical applications.
- To explore the structure-activity relationships of identified PPM1D inhibitors.
- To evaluate the in vivo efficacy of novel PPM1D inhibitors in modulating the DDR and p53 pathways.
Main Methods:
- High-throughput screening of 600,000 compounds using a PPM1D displacement assay.
- Lead optimization utilizing custom assays to assess PPM1D, p53, and DDR modulation.
- In vivo bioluminescent imaging to monitor p53 activation and compare compound efficacy.
Main Results:
- A hit series of compounds with nanomolar PPM1D inhibitory activity was identified.
- Structure-activity relationship studies defined key molecular features for PPM1D inhibition.
- A lead compound, distinct in chemical structure, demonstrated comparable in vivo p53 activation to established PPM1D inhibitors.
Conclusions:
- The study successfully yielded multiple allosteric inhibitors of PPM1D.
- This work enhances the understanding of PPM1D as a druggable target for cancer therapy.
- The developed screening and evaluation platform is adaptable for studying other DDR and p53 modulators.
