Amphista™ is developing an orally bioavailable, selective SMARCA2 Targeted Glue™ degrader, targeting tumors with loss-of-function SMARCA4 mutations, including Non-Small Cell Lung Cancer (NSCLC).

SMARCA2 and SMARCA4 are functionally redundant catalytic subunits of the BAF chromatin remodelling complex. In tumors harbouring SMARCA4 loss-of-function mutations, cells become dependent on SMARCA2 for BAF complex function and survival. SMARCA4 mutations occur in approximately 5% of solid tumors and up to 10% of NSCLC, creating a vulnerability that selective SMARCA2 degradation can exploit through synthetic lethality, with a favourable therapeutic index over SMARCA4-expressing normal tissue.

Amphista’s SMARCA2 degraders act through a novel DCAF16-mediated mechanism, and deliver class leading selectivity over SMARCA4. Our degraders have demonstrated deep in vivo SMARCA2 degradation following oral dosing.

Amphista™ is developing an orally bioavailable pan-TEAD Targeted Glue™ degrader, targeting Hippo pathway-driven cancers including mesothelioma and combination strategies for Non Small Cell Lung Cancer (NSCLC).

TEAD transcription factors are critical effectors of the Hippo signalling pathway, regulating gene transcription when bound to coactivators YAP and TAZ. Hippo pathway dysregulation leads to increased TEAD target gene transcription, driving tumorigenesis in solid tumors such as mesothelioma, and underpinning resistance mechanisms in NSCLC.

Amphista’s TEAD degraders act through a novel FBXO22-mediated mechanism, delivering best-in-class pharmacology with deep and rapid target degradation and robust in vivo oral efficacy in a mesothelioma xenograft model. The degradation-based modality, combined with TEAD’s long half-life, results in extended pharmacodynamic effects enabling an efficacious once-every-three-day in vivo dosing schedule.

Read more about the rational and systematic optimization of our early TEAD Targeted Glues™.