Identification of small molecule inhibitors of PPM1D using an integrated drug discovery platform

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 <i>in vivo</i> 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 <i>in vivo</i> 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.

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Publication Details

Journal
iScience
Published
2025-02-20
DOI
https://doi.org/10.1016/j.isci.2025.112069
Primary Topic
Biochemical and Molecular Research
Type
article
Field-Weighted Citation Impact
0.00

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article

Identification of small molecule inhibitors of PPM1D using an integrated drug discovery platform

Nancy Dumont, David C. McKinney, Colin W. Garvie, Jason S. Rush et al.
iScience
Biochemical and Molecular Research
article

Identification of small molecule inhibitors of PPM1D using an integrated drug discovery platform

Nancy Dumont, David C. McKinney, Colin W. Garvie, Jason S. Rush, Mateusz Szuchnicki, Josephine Kahn, Murugappan Sathappa, Wei Jiang, Florence F. Wagner, Cerise Raffier, Subrata Shaw, Alexandra E. Gould, Cameron Schluter, Zachary C. Murphy, Ritu Singh, Carol Khodier, Adam S. Sperling, Adam Skepner, Peter G. Miller, Yu Xiao, Ni Yan, John Kim
article en

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 <i>in vivo</i> 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 <i>in vivo</i> 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.

iScienceVol. 28(3)
Broad Institute (US), Brigham and Women's Hospital (US), Harvard University (US), Dana-Farber Cancer Institute (US), Center for Cancer Research (US)
Edward P. Evans Foundation, National Cancer Institute
Openalex Percentile: Top 97%
Biochemical and Molecular Research
DOIOpen Access PDFOpenAlex
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