Pathological signaling requires protein-protein interactions (PPIs)
a) Many selective ligands fail to completely suppress signaling
b) PPIs are difficult to disrupt
AP Interceptors can transform ineffective ligands into signaling complex assembly disruptors
All oncogenic drivers physically partner with other proteins to invoke aberrant signaling. Selective disruption of these protein-protein complexes has proven difficult with small molecules that fail to inhibit non-catalytic roles that support oncogenic growth. In contrast, Apertor’s Interceptors induce proximity with an abundant intracellular protein (FKBP12) to a target complex, effectively attenuating oncogenic signaling by steric obstruction.
Oncology Targets with unmet needs
Computational Modeling: Interceptor & Obstructor Target Ligand & Target
Chemical Biology: On/off target Phenotypic effects, etc.
Synthetic Biology & Chemistry: Evolution of Interceptors
Interceptors offer multiple advantages over modalities that degrade proteins via proximity induction with E3 ligases (i.e. PROTACS). Interceptors can obstruct targets that are inaccessible to protein degraders either due to their cellular location (i.e. in the nucleus) or their structure (i.e. they lack the correct amino acid for tagging by the E3 ligase), thus opening up new targets for disruption.
Additionally, Interceptors selectively target disease-relevant protein-protein interactions while sparing other essential functions, in contrast to the potential unwanted effects stemming from target degradation. Interceptors also retain activity across a broader range of drug concentrations compared with degraders, given the high cellular concentration of FKBP12 in most cells.
