Designing small molecule internalization inducer
Challenging targeting TROP2 with small molecules
to promote its internalization
3
novel binding pockets targeted
(8M stock library screened)
7
potent hits identified
(54 compounds tested)
3
compounds promote
TROP2 internalization
01/ Background
- TROP2 is a critical target inimmuno-oncology, validatedby antibodies but lacking small molecule ligands and binding pockets.
- The goal is to promote TROP2’s internalization by small molecules.
02/ Challenges
- No small molecule binders exist.
- No small molecule binding pockets are known.
- Structural diversity of hits is required.
03/ Methodology
- Utilized Receptor.AI’s pocket identification pipeline.
- Performed virtual screening of 8M compounds (stock library).
- Bio-layer interferometry assay used to identify hit compounds.
- Differential scanningfluorimetry assay used to confirm hits.
04/ Results
- 3 binding pockets for small molecules identified.
- 54 compounds subject to experimental validation after
virtual screening against all 3 identified binding pockets. - 15 potential hit compounds identified with BLI assay.
- 7 potent hit compounds confirmed with DSF assay
- Hits are of 3 different chemical classes.
*Binding mode of one of the top compounds
