Targeting GDP-Dissociation Inhibitor Beta (GDI2) with a Benzo[a]quinolizidine Library to Induce Paraptosis for Cancer Therapy.

ABSTRACT: Inducing paraptosis, a nonapoptotic form of cell death, has great therapeutic potential in cancer therapy, especially for drug-resistant tumors. However, the specific molecular target(s) that trigger paraptosis have not yet been deciphered yet. Herein, by using activity-based protein profiling, we identified the GDP-dissociation inhibitor beta (GDI2) as a manipulable target for inducing paraptosis and uncovered benzo[a]quinolizidine BQZ-485 as a potent inhibitor of GDI2 through the interaction with Tyr245. Comprehensive target validation revealed that BQZ-485 disrupts the intrinsic GDI2-Rab1A interaction, thereby abolishing vesicular transport from the endoplasmic reticulum (ER) to the Golgi apparatus and initiating subsequent paraptosis events including ER dilation and fusion, ER s

SUBMITTER: Sun Y 

PROVIDER: S-EPMC10598831 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature