Background
GPX4 is an enzyme crucial for cellular antioxidant defense, protecting against lipid peroxidation and regulating ferroptosis, a programmed cell death implicated in various diseases.
Challenge
- Highly potent and specific GPX4 inhibitors remain scarce for molecular design and screening reference.
- The shallow and flat binding pocket of GPX4 poses significant chnallenges for non-covalent small molecule inhibitor drug design.
- Its undruggable characteristics urgently require the screening of lead ofompounds from a vast compound library.
Key Results
- Quantum physics-based model featuring high accuracy and throughput to probe key pharmacophores with no reference compounds reported.
- The designed compounds featuring key pharmacophores were selecteed from the 6.4*1014 accessible space by automation-compatible chemistry.
- Proprietary automation technologies rapidly synthesize a two-step synthesiof 124 library compounds.
- 3 novel non-covalent small molecule inhibitors show IC50 <10μM by cormmercial kit.
