GDC-0879, a BRAFV600E Inhibitor, Protects Kidney Podocytes from Death

Jonas Sieber; Nicolas Wieder; Abbe Clark; Manuel Reitberger; Sofia Matan; Jeannine Schoenfelder; Jianming Zhang; Anna Mandinova; Joshua Adam Bittker; Juan Gutierrez; Ozan Aygün; Namrata Udeshi; Steven Carr; Peter Mundel; Andreas Werner Jehle; Anna Greka

doi:10.1016/j.chembiol.2017.11.006

GDC-0879, a BRAF^V600E Inhibitor, Protects Kidney Podocytes from Death

Cell Chem Biol. 2018 Feb 15;25(2):175-184.e4. doi: 10.1016/j.chembiol.2017.11.006. Epub 2017 Dec 14.

Authors

Affiliations

¹ Department 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.
² 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.
³ Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02129, USA.
⁴ The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
⁵ Department of Biomedicine, Molecular Nephrology, University of Basel, Basel 4031, Switzerland.
⁶ 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. Electronic address: [email protected].

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^V600E 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.

Keywords: BRAF; ER stress; ERK; MAPK; SB-682330; cell death; forskolin; glomerular disease; kidney disease; melanoma; post-mitotic cells.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Cell Death / drug effects
Colforsin / chemistry
Colforsin / pharmacology
Humans
Indenes / chemistry
Indenes / pharmacology*
Kidney Diseases / drug therapy*
Kidney Diseases / metabolism
Kidney Diseases / pathology
MAP Kinase Signaling System / drug effects
Podocytes / drug effects*
Podocytes / metabolism
Podocytes / pathology
Pyrazoles / chemistry
Pyrazoles / pharmacology*
Signal Transduction / drug effects
Thapsigargin / antagonists & inhibitors
Thapsigargin / pharmacology

Substances

2-(4-(1-(hydroxyimino)-2,3-dihydro-1H-inden-5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)ethan-1-ol
Indenes
Pyrazoles
Colforsin
Thapsigargin

Abstract

Publication types

MeSH terms

Substances

Grants and funding