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Published on: May 15, 2019
Development of small-molecule PUMA inhibitors for mitigating radiation-induced cell death
Gabriela Mustata1, Mei Li, Nicki Zevola
1University of Pittsburgh School of Medicine, Department of Computational & Systems Biology, HillmanCancer Center Research Pavilion, 5117 Centre Ave, Pittsburgh, PA 15213, USA.
Abstract:
PUMA (p53 upregulated modulator of apoptosis) is a Bcl-2 homology 3 (BH3)-only Bcl-2 family member and a key mediator of apoptosis induced by a wide variety of stimuli. PUMA is particularly important in initiating radiation-induced apoptosis and damage in the gastrointestinal and hematopoietic systems. Unlike most BH3-only proteins, PUMA neutralizes all five known antiapoptotic Bcl-2 members though high affinity interactions with its BH3 domain to initiate mitochondria-dependent cell death. Using structural data on the conserved interactions of PUMA with Bcl-2-like proteins, we developed a pharmacophore model that mimics these interactions. In silico screening of the ZINC 8.0 database with this pharmacophore model yielded 142 compounds that could potentially disrupt these interactions. Thirteen structurally diverse compounds with favorable in silico ADME/Toxicity profiles have been retrieved from this set. Extensive testing of these compounds using cell-based and cell-free systems identified lead compounds that confer considerable protection against PUMA-dependent and radiation-induced apoptosis, and inhibit the interaction between PUMA and Bcl-xL.
Insights
Researchers identified compounds that protect against radiation-induced apoptosis by disrupting PUMA protein interactions. These findings offer potential therapeutic strategies for mitigating radiation damage.
Area of Science:
- Molecular Biology
- Biochemistry
- Pharmacology
Background:
- PUMA (p53 upregulated modulator of apoptosis) is a critical BH3-only protein mediating apoptosis.
- PUMA is vital for radiation-induced apoptosis, especially in the gastrointestinal and hematopoietic systems.
- PUMA inhibits all five antiapoptotic Bcl-2 members, initiating mitochondria-dependent cell death.
Purpose of the Study:
- To develop a pharmacophore model based on PUMA's interactions with Bcl-2 proteins.
- To identify small molecules capable of disrupting PUMA-Bcl-2 interactions.
- To find lead compounds that protect against PUMA-dependent and radiation-induced apoptosis.
Main Methods:
- Developed a pharmacophore model using structural data of PUMA-Bcl-2 interactions.
- Performed in silico screening of the ZINC 8.0 database.
- Retrieved and tested compounds for in vitro and cell-based assays.
Main Results:
- Identified 142 potential compounds disrupting PUMA-Bcl-2 interactions.
- Selected 13 diverse compounds with favorable ADME/Toxicity profiles.
- Discovered lead compounds protecting against PUMA-dependent and radiation-induced apoptosis.
- Demonstrated inhibition of PUMA-Bcl-xL interaction by lead compounds.
Conclusions:
- The developed pharmacophore model effectively identified potential PUMA inhibitors.
- Lead compounds show promise in protecting against radiation-induced apoptosis.
- These compounds may serve as a basis for novel radioprotective agents.
