The development of a multigram synthesis of 3-exo-isopropylbicyclo[2.2.1]heptan-2-endo-amine hydrochloride (1) (also known as BRD4780 and AGN-192403) is described. The process involves protection of the amine as 4-nitrobenzyl carbamate, pNZ, which enables chiral SFC chromatography. The absolute configuration (AC) of the individual enantiomers has been determined by Mosher's amide method, VCD spectroscopy, and X-ray crystallography. We highlight the VCD approach as a rapid and effective means of AC determination that can be deployed directly on the target compounds.

01 Jul 2019·CellQ1 · BIOLOGY

Small Molecule Targets TMED9 and Promotes Lysosomal Degradation to Reverse Proteinopathy

Q1 · BIOLOGY

Article

Author: Gregory Papagregoriou ; Seth L. Alper ; Eric S. Lander ; Constantinos Deltas ; Savithri Kota ; Juan Gutierrez ; Michelle Melanson ; Kate Hartland ; Julie Roignot ; Nicolas Wieder ; Anthony J. Bleyer ; Todd A. Carter ; Andreas Gnirke ; Eriene-Heidi Sidhom ; Ana Rivadeneira ; Eva Kohnert ; Moran Dvela-Levitt ; Veronika Barešova ; Stanislav Kmoch ; Florence Wagner ; Monica S. Montesinos ; Nareh Sahakian ; Lucienne Ronco ; Mark Roth ; Astrid Weins ; Rebecca Hughey ; Myriam Heiman ; Jane C.-H. Hsu ; Abbe R. Clark ; Rebecca Thompson ; Maheswarareddy Emani ; Anna Greka ; Martina Živná ; David McKinney ; Todd R. Golub ; Esther Elonga ; Johannes Schlondorff ; Maria Kost-Alimova

Intracellular accumulation of misfolded proteins causes toxic proteinopathies, diseases without targeted therapies. Mucin 1 kidney disease (MKD) results from a frameshift mutation in the MUC1 gene (MUC1-fs). Here, we show that MKD is a toxic proteinopathy. Intracellular MUC1-fs accumulation activated the ATF6 unfolded protein response (UPR) branch. We identified BRD4780, a small molecule that clears MUC1-fs from patient cells, from kidneys of knockin mice and from patient kidney organoids. MUC1-fs is trapped in TMED9 cargo receptor-containing vesicles of the early secretory pathway. BRD4780 binds TMED9, releases MUC1-fs, and re-routes it for lysosomal degradation, an effect phenocopied by TMED9 deletion. Our findings reveal BRD4780 as a promising lead for the treatment of MKD and other toxic proteinopathies. Generally, we elucidate a novel mechanism for the entrapment of misfolded proteins by cargo receptors and a strategy for their release and anterograde trafficking to the lysosome.

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Indication	Highest Phase	Country/Location	Organization	Date
Medullary Cystic Kidney Disease	Preclinical	US	The Broad Institute, Inc.	24 Jul 2019

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