molecules of the month

Compound 13 (GSK716)

mutant alpha-1-antitrypsin folding corrector

sub-µM in cell, high predicted human %F

from 2T component DEL + SBDD

Bioorg. Med. Chem. Lett., Mar. 19, 2021

GlaxoSmithKline, Stevenage, UK / UCL

1 min read

The GlaxoSmithKline (GSK) Z α1-antitrypsin stabilizer (“compound 13,” GSK716) acts by blocking the formation of polymers within the endoplasmic reticulum of hepatocytes for treatment of α1-antitrypsin deficiency. It was identified through a DNA-encoded library screen with a nominal diversity of 2 trillion components. Compound 13 showed an excellent selectivity profile toward α1-antitrypsin. The 1 mg/kg i.v. infusion of compound 13 demonstrated moderate bioavailability in rat and was predicted to have high oral bioavailability in human. This molecule is interesting as the starting point came from a DEL screen and has a rare corrector mechanism of action.

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