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Publications & Presentations

STX-478, a Mutant-Selective, Allosteric PI3Kα Inhibitor Spares Metabolic Dysfunction and Improves Therapeutic Response in PI3Kα-Mutant Xenografts

Phosphoinositide 3-kinase α (PIK3CA) is one of the most mutated genes across cancers, especially breast, gynecologic, and head and neck squamous cell carcinoma tumors.

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Identification of STX-241, a potential best-in-class, CNS-penetrant, and highly mutant-selective EGFR inhibitor with activity on osimertinib-resistant C797x mutations

EGFR mutations are well validated clinical targets in non-small cell lung cancer (NSCLC). Osimertinib, a highly-selective EGFR mutation-targeting covalent drug, is increasingly used in the first line setting for patients with NSCLC bearing EGFR L858R mutation or exon 19 deletions (ex19del).

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“Precision Oncology Comes of Age : Designing Best-in-Class Small Molecules by Integrating Two Decades of Advances in Chemistry, Target Biology, and Data Science”

Small molecule drugs have enabled the practice of Precision Oncology for genetically defined patient populations since the first approval of Gleevec in 2001. Scientific and technology advances over this 20-year period have driven the evolution of cancer biology, medicinal chemistry, and computational data sciences.

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STX-478, a mutant-selection PI3Kα inhibitor clinical candidate with a best-in-class-profile

Selective targeting of mutant PI3Kα is expected to improve anti-tumor activity and reduce toxicities associated with inhibiting the wild-type enzyme in normal tissues, which are frequently observed with alpelisib, the only approved drug for this target.

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Identification of STX-721, an EGFR exon 20 mutant inhibitor with superior selectivity and a potential best-in-class profile

EGFR mutations are well validated clinical targets in NSCLC. Osimertinib, a highly-selective EGFR mutation-targeting drug, achieves an objective response rate of ~80% against cancers with L858R or exon 19 deletion. In contrast, patients with EGFR exon 20 insertion mutations exhibit response rates to currently approved or investigational therapies between 28%-52%. The suboptimal efficacy of existing EGFR inhibitors for patients with exon 20 mutations is likely due to poor mutant versus wild-type EGFR selectivity.

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Discovery and characterization of a PI3Kα H1047X mutant selective inhibitor with a best-in-class profile

PI3Kα is highly mutated in cancer with the most prevalent mutation, H1047R, occurring in approximately 14% of breast cancers. This mutation causes hyperactivation of lipid kinase activity and downstream AKT signaling.
Therapeutic proof-of-concept for targeting PI3Ka mutations was established with alpelisib, an alpha-selective PI3K inhibitor that is equipotent against wild-type and mutant forms. However, the therapeutic benefit of alpelisib is limited by the inhibition of wild-type PI3Kα in normal tissues, resulting in dose-limiting toxicities including hyperglycemia.

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