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GDC-0879, a BRAFV600E Inhibitor, Protects Kidney Podocytes from Death
Jonas Sieber1, Nicolas Wieder2, Abbe Clark2
1Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Abstract:
Progressive kidney diseases affect approximately 500 million people worldwide. Podocytes are terminally differentiated cells of the kidney filter, the loss of which leads to disease progression and kidney failure. To date, there are no therapies to promote podocyte survival. Drug repurposing may therefore help accelerate the development of cures in an area of tremendous unmet need. In a newly developed high-throughput screening assay of podocyte viability, we identified the BRAFV600E inhibitor GDC-0879 and the adenylate cyclase agonist forskolin as podocyte-survival-promoting compounds. GDC-0879 protects podocytes from injury through paradoxical activation of the MEK/ERK pathway. Forskolin promotes podocyte survival by attenuating protein biosynthesis. Importantly, GDC-0879 and forskolin are shown to promote podocyte survival against an array of cellular stressors. This work reveals new therapeutic targets for much needed podocyte-protective therapies and provides insights into the use of GDC-0879-like molecules for the treatment of progressive kidney diseases.
Insights
Researchers identified GDC-0879 and forskolin as compounds that promote podocyte survival, offering new therapeutic avenues for progressive kidney diseases. These findings address a critical unmet need for treatments protecting kidney filter cells.
Area of Science:
- Nephrology
- Pharmacology
- Cell Biology
Background:
- Progressive kidney diseases impact 500 million globally, with podocyte loss leading to kidney failure.
- No current therapies exist to enhance podocyte survival, highlighting a significant unmet medical need.
- Drug repurposing presents a viable strategy to expedite the development of novel kidney disease treatments.
Purpose of the Study:
- To identify compounds that promote podocyte survival using a high-throughput screening assay.
- To investigate the mechanisms by which identified compounds protect podocytes from injury.
- To evaluate the potential of these compounds as therapeutic agents for progressive kidney diseases.
Main Methods:
- Development of a high-throughput screening assay to assess podocyte viability.
- Identification of GDC-0879 (a BRAFV600E inhibitor) and forskolin (an adenylate cyclase agonist) as podocyte-protective compounds.
- Mechanistic studies involving the MEK/ERK pathway and protein biosynthesis.
Main Results:
- GDC-0879 demonstrated podocyte protection via paradoxical MEK/ERK pathway activation.
- Forskolin promoted podocyte survival by attenuating protein biosynthesis.
- Both compounds effectively protected podocytes against various cellular stressors.
Conclusions:
- GDC-0879 and forskolin represent promising candidates for podocyte-protective therapies.
- This study identifies novel therapeutic targets for progressive kidney diseases.
- Findings support the exploration of GDC-0879-like molecules for treating kidney filter damage.
