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bioRxiv
BIORXIV
bioRxiv
Cold Spring Harbor Laboratory

10.1101/2024.05.20.595001
preprint
1
Article
Identification of Small Molecule Inhibitors of PPM1D Using a Novel Drug Discovery Platform
Jiang Wei
Shaw Subrata
Rush Jason
Dumont Nancy
Kim John
Singh Ritu
Skepner Adam
Khodier Carol
Raffier Cerise
Yan Ni
Schluter Cameron
Yu Xiao
Szuchnicki Mateusz
Sathappa Murugappan
Kahn Josephine
Sperling Adam S.
McKinney David C.
Gould Alexandra E.
Garvie Colin W.
Miller Peter G.
21 5 2024
2024.05.20.595001http://biorxiv.org/lookup/doi/10.1101/2024.05.20.595001
nihpp-2024.05.20.595001.pdf
ABSTRACT

Protein phosphatase, Mg 2+ /Mn 2+ dependent 1D (PPM1D), is a serine/threonine phosphatase that is recurrently activated in cancer, regulates the DNA damage response (DDR), and suppresses the activation of p53. Consistent with its oncogenic properties, genetic loss or pharmacologic inhibition of PPM1D impairs tumor growth and sensitizes cancer cells to cytotoxic therapies in a wide range of preclinical models. Given the therapeutic potential of targeting PPM1D specifically and the DDR and p53 pathway more generally, we sought to deepen our biological understanding of PPM1D as a drug target and determine how PPM1D inhibition differs from other therapeutic approaches to activate the DDR. We performed a high throughput screen to identify new allosteric inhibitors of PPM1D, then generated and optimized a suite of enzymatic, cell-based, and in vivo pharmacokinetic and pharmacodynamic assays to drive medicinal chemistry efforts and to further interrogate the biology of PPM1D. Importantly, this drug discovery platform can be readily adapted to broadly study the DDR and p53. We identified compounds distinct from previously reported allosteric inhibitors and showed in vivo on-target activity. Our data suggest that the biological effects of inhibiting PPM1D are distinct from inhibitors of the MDM2-p53 interaction and standard cytotoxic chemotherapies. These differences also highlight the potential therapeutic contexts in which targeting PPM1D would be most valuable. Therefore, our studies have identified a series of new PPM1D inhibitors, generated a suite of in vitro and in vivo assays that can be broadly used to interrogate the DDR, and provided important new insights into PPM1D as a drug target.
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pmc
