Small molecule FICD inhibitors suppress endogenous and pathologic FICD-mediated protein AMPylation.
Bhaskar K ChatterjeeMaroof AlamArghya ChakravortyShannon M LacyJason RechCharles L Brooks IiiPeter D ArvanMatthias C TruttmannPublished in: bioRxiv : the preprint server for biology (2024)
The AMP transferase, FICD, is an emerging drug target finetuning stress signaling in the endoplasmic reticulum (ER). FICD is a bi-functional enzyme, catalyzing both AMP addition (AMPylation) and removal (deAMPylation) from the ER resident chaperone BiP/GRP78. Despite increasing evidence linking excessive BiP/GRP78 AMPylation to human diseases, small molecules to inhibit pathogenic FICD variants are lacking. Using an in-vitro high-throughput screen, we identify two small-molecule FICD inhibitors, C22 and C73. Both molecules significantly inhibit FICD-mediated BiP/GRP78 AMPylation in intact cells while only weakly inhibiting BiP/GRP78 deAMPylation. C22 and C73 also efficiently inhibit pathogenic FICD variants and improve proinsulin processing in β cells. Our study identifies and validates FICD inhibitors, highlighting a novel therapeutic avenue against pathologic protein AMPylation.
Keyphrases
- endoplasmic reticulum
- small molecule
- induced apoptosis
- endoplasmic reticulum stress
- high throughput
- protein protein
- cell cycle arrest
- signaling pathway
- neoadjuvant chemotherapy
- endothelial cells
- copy number
- cell surface
- patient safety
- emergency department
- gene expression
- estrogen receptor
- cell death
- single cell
- breast cancer cells
- pi k akt
- heat shock protein
- heat shock