We select targets with clear opportunity for a precision medicine strategy to address three target categories in what we consider “therapeutic white spaces” of underserved populations.
Validated oncogene targets
Novel cancer targets
Mut-Sel H1047 PI3Kα
STX-478 is designed to be a wild-type-sparing, oral inhibitor of kinase-domain-mutant PI3Kα capable of penetrating the blood-brain barrier.
PI3Kα is an established cancer target and one of the most highly mutated targets in cancer, particularly in solid tumors. Mutations in the kinase domain and in particular at the H1047 residue represent the highest frequency mutations in PI3Kα. Kinase domain PI3Kα mutations have been validated as bona fide drivers of cancer development through numerous preclinical studies and clinical trials published by third parties. Because of the frequency of mutations in PI3Kα in driving tumor progression, the target has been a high priority for drug discovery for several years.
However, the treatments currently approved suffer from limited efficacy, poor tolerability, and an inability to cross the Central Nervous System’s blood-brain barrier, rendering them ineffective for people with brain metastases.
We have demonstrated superior in vitro selectivity in multiple head-to-head preclinical studies and dose-dependent anti-tumor activity in animal models at well-tolerated doses without causing metabolic dysregulation that leads to hyperinsulinemia and hyperglycemia — a key challenge associated with targeting this mutation. In addition, we have incorporated optimized overall pharmaceutical properties including low peak-to-trough variation together with high intrinsic selectivity to create our clinical candidate.
Mut-Sel EGFR Exon 20 insertion
STX-721 is designed to selectively target exon 20 insertion mutations in EGFR, a well-known, clinically validated driver oncogene in non-small cell lung cancer (“NSCLC”).
EGFR exon 20 insertion mutations have been validated as bona fide drivers of cancer development through numerous preclinical studies and clinical trials published by third parties.
While commercially available small molecules have been able to inhibit most EGFR mutations, exon 20 insertion mutations that change the structure of the protein and force it in an activated state are generally resistant to these agents, leaving those patients with a much poorer prognosis. STX-721 exhibits a selectivity profile that could translate into higher response rates and lower toxicities than are associated with other compounds targeting exon 20 insertion mutant EGFR-driven NSCLC.
We have demonstrated superior selectivity in multiple head-to-head preclinical studies versus other agents, and dose-dependent anti-tumor activity in xenograft models at well-tolerated doses.
Best-in-class Discovery Programs Against Validated Oncogene Targets
Targets include mutant cancer drivers
First-in-Class Discovery Programs Against Undruggable Targets
Targets are novel synthetic lethal proteins & transcription factors, including those part of our collaboration with AstraZeneca
First-in-Class Discovery Programs Against Novel Cancer Targets
Targets exploit common loss-of-heterozygosity (LOH) events, amongst other categories