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Ref Type Abstract
Authors John R. MacDougall; John Bradley; Raymond Mak; Neil Dhawan; Wei Chen
Title Abstract 4946: TOS-358, a first-in-class covalent PI3Kα inhibitor, demonstrates superior efficacy and does not induce significant hyperglycemia at efficacious doses in multiple animal models
Abstract Text PI3Kα is frequently mutated in a variety of cancer types, and the PI3K-AKT signaling axis also plays a role in insulin signaling and glucose homeostasis. TOS-358 is a highly selective first-in-class covalent inhibitor of PI3Kα and is currently in clinical development in multiple solid malignancies. Interestingly, TOS-358 potently and specifically inhibits PI3Kα deeply and durably, but does not induce significant hyperglycemia in a variety of animal models. TOS-358 has consistently demonstrated superior efficacy comparing to reversible PI3Kα inhibitors (ATP-competitive and Allosteric) across 30+ different PDX and CDX mutant PI3Kα dependent cancer models. Detailed metabolic studies also revealed TOS-358 does not induce significant hyperglycemia effects in mice, rats and dogs at efficacious doses, which mirrors previous finding that show that PI3Kα knockout does not induce significant hyperglycemia. Furthermore, we elucidate that previous reversible PI3Kα inhibitors lead to dramatic hyperglycemia due to their potent inhibition of multiple PI3K isoforms at effective concentrations of the molecules in a cellular setting. This data reveals that highly specific and potent covalent inhibition of PI3Kα leads to dramatically superior efficacy and an improved safety profile.


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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
PIK3CA mutant Advanced Solid Tumor predicted - sensitive TOS-358 Preclinical - Pdx Actionable In a preclinical study, TOS-358 demonstrated efficacy in patient-derived xenograft (PDX) and cell line xenograft models harboring PIK3CA mutations (Cancer Res (2023) 83 (7_Supplement): 4946). detail...