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Cell Chem Biol DOI:10.1016/j.chembiol.2017.11.006

GDC-0879, a BRAF Inhibitor, Protects Kidney Podocytes from Death.

Publication TypeJournal Article
Year of Publication2018
AuthorsSieber, J, Wieder, N, Clark, A, Reitberger, M, Matan, S, Schoenfelder, J, Zhang, J, Mandinova, A, Bittker, JAdam, Gutierrez, J, Aygun, O, Udeshi, N, Carr, S, Mundel, P, Jehle, AWerner, Greka, A
JournalCell Chem Biol
Volume25
Issue2
Pages175-184.e4
Date Published2018 02 15
ISSN2451-9448
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 BRAF 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.

DOI10.1016/j.chembiol.2017.11.006
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/29249695?dopt=Abstract

Alternate JournalCell Chem Biol
PubMed ID29249695
PubMed Central IDPMC5819995
Grant ListR01 DK095045 / DK / NIDDK NIH HHS / United States
R01 DK099465 / DK / NIDDK NIH HHS / United States