molecules of the month

“compound 1”

avb6 integrin inhibitor + lysosomal degrader

in vitro degradation, Ph. I completed, discont.

derived from prior integrin inhibitors

J. Pharmacol. Exp. Ther., Jan. 26, 2021

GlaxoSmithKline, Stevenage, UK

Chemical structure of "compound 1" GSK αvβ6 integrin inhibitor (GSK 3008348)
1 min read

The GSK αvβ6 integrin inhibitor, “compound 1,” or GSK 3008348 is a previously reported IPF clinical candidate that is a picomolar binder to αvβ6 with slow dissociation kinetics. The recent report highlights the fact that the compound results in prolonged effects in cells by triggering integrin internalization and lysosomal degradation. While this phenomena of small molecule-induced receptor internalization/degradation has been characterized in other transmembrane receptors such as GPCRs, it hasn’t been well-studied in integrins. Small molecule integrin modulators are seeing renewed interest for indications such as fibrosis, and this induced lysosomal degradation pharmacology is worth keeping in the mental toolbox for targeting integrins and other transmembrane proteins.

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