Amphista Therapeutics, a leader in the discovery of next-generation targeted protein degradation (TPD) medicines, has disclosed first data on its SMARCA2 programme, including demonstrating exquisite selectivity of its sequentially bifunctional Targeted Glues for SMARCA2 compared with the closely related homolog: SMARCA4.
Amphista’s SMARCA2 Targeted Glues have demonstrated the following benefits.
- Novel mechanism of degradation: Amphista’s SMARCA2 Targeted Glue series induces degradation via induction of the E3 ligase DCAF16, a novel mechanism of degradation that goes beyond traditional TPD technologies.
- Exquisite selectivity compared with SMARCA4: With the generation of high-resolution cryo-EM, Amphista has learnt the structural basis for selectivity compared with SMARCA4 and has been able to design molecules with near complete selectivity for SMARCA2, with <5% SMARCA4 degradation observed.
- Highly specific degradation of SMARCA2: Global proteomics profiling demonstrates statistically significant degradation of SMARCA2 versus more than 8000 other proteins, including SMARCA4.
- Exceptional degradation kinetics: Amphista’s Targeted Glues can potently degrade >95% SMARCA2 within 4 hours.
- CNS penetrance: Amphista has identified a series of SMARCA2 degraders that have demonstrated CNS penetration in vivo. This offers the potential to develop medicines that can treat CNS metastasis, which frequently occur in lung cancer.
Louise Modis, Chief Scientific Officer of Amphista Therapeutics, said: “We are excited by the quality of the profile we have been able to achieve with our selective SMARCA2 degraders."
"The bar for success is very high in this area and we believe achieving sufficient selectivity compared with SMARCA4 is absolutely critical to generate a best-in-class molecule."
"With the extensive deployment of cutting-edge cryo-EM structures, we have been able to do just that — to generate Targeted Glues that degrade SMARCA2, and only SMARCA2, at sustained timepoints. In addition, we believe the impressive degradation kinetics we can achieve with our technology will give us a significant advantage clinically.”
Amphista plans to present data from its SMARCA2 Targeted Glue programme at a key forthcoming scientific conference.