Structural determinants of PERK inhibitor potency and selectivity.

Area of Science:

• Biochemistry
• Molecular Biology
• Cancer Research

Background:

• The unfolded protein response (UPR) is vital for cell survival during endoplasmic reticulum stress and contributes to tumor progression.
• Pancreatic endoplasmic reticulum kinase (PERK), a key UPR transducer, is implicated as a potential cancer drug target due to its role in tumor growth.
• No specific small molecule inhibitors targeting the PERK pathway have been identified to date.

Purpose of the Study:

• To identify specific pair-wise receptor-ligand atomic contacts that confer selective inhibition of PERK.
• To understand the structure-activity relationships governing PERK inhibition for rational drug design.

Main Methods:

• Virtual library screening to identify compounds selectively inhibiting PERK-mediated phosphorylation in vitro.
• Structure-activity hypothesis testing to validate identified inhibitory mechanisms.
• Analysis of specific kinase active site contacts, including van der Waals interactions, activation loop interactions, and electrostatic complementarity.

Main Results:

• Potent and selective PERK inhibitors were identified, utilizing three critical kinase active site contacts.
• A strong van der Waals contact with PERK residue Met7, interactions with the N-terminal activation loop, and electrostatic complementarity to Asp144 were essential for inhibition.
• The interaction with the activation loop was found to be specifically required for PERK selectivity.

Conclusions:

• Understanding the identified structure-activity relationships is key to accelerating the rational design of PERK inhibitors.
• These findings provide a foundation for developing targeted cancer therapies aimed at the PERK-mediated UPR pathway.