STX-478, A Selective PI3Kα Inhibitor
1. Background
Scorpion Therapeutics is a precision oncology company founded in February 2020 by a preeminent group of scientists from Harvard University/Massachusetts General Hospital – Keith Flaherty, MD, Gaddy Getz, Ph.D. and Liron Bar-Peled, Ph.D. The company has raised $270M in Series A and Series B financings led by blue-chip investors, including Atlas Venture, Boxer Capital of Tavistock Group, EcoR1 Capital, LLC, Omega Funds, and Vida Venture.
STX-478, Scorpion’s highly differentiated, allosteric and central nervous-system (“CNS”) penetrant inhibitor of mutant phosphoinositide-3-kinase alpha (“PI3Kα”), for the treatment of HR+/HER2- breast cancer and other solid tumors. The Phase 1/2 clinical trial will evaluate STX-478 as a monotherapy in a variety of solid tumors including breast and gynecological cancers, head and neck squamous cell carcinoma (“HNSCC”) and others, as well as a monotherapy and in combination with approved agents in patients with HR+/HER2- breast
cancer.
STX-478 is designed to improve outcomes in patients harboring prevalent PI3Kα mutations in their tumors and has shown activity in both kinase and helical domain mutated tumors in preclinical models. PI3Kα mutations are among the most prevalent drivers of cancer, occurring in over 166,000 patients per year with breast, gynecological and head and neck cancers in the United States alone. The frequency of PI3Kα mutations and the scarcity of available treatment options has made the target a high priority for drug discovery
First-in-Human Study of STX-478 as Monotherapy and in Combination With Other Antineoplastic Agents in Participants With Advanced Solid Tumors is recruiting (NCT05768139)
2. Chemistry Structure and synthesis route of STX-478.
a) Intermediates of STX-478
b) patents and related literature.
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WO2022265993A1
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Cancer Res (2023) 83 (5_Supplement): P4-07-04
3. Activity of STX-478
a) Model of action
STX-478 is designed to improve outcomes in patients harboring prevalent PI3Kα mutations in their tumors and has shown activity in both kinase and helical domain mutated tumors in preclinical models. PI3Kα mutations are among the most prevalent drivers of cancer, occurring in over 166,000 patients per year with breast, gynecological and head and neck cancers in the United States alone. The frequency of PI3Kα mutations and the scarcity of available treatment options has made the target a high priority for drug discovery
b) In vitro and in vivo efficacy
1. STX-478 is a potent, highly selective mutant PI3Ka inhibitor in cellular assays
2. Combinatorial synergy between STX-478 and relevant co-treatments in vitro
3. Efficacy of STX-478 in combination with fulvestrant in T47D xenograft tumors
4. STX-478 was efficacious and well tolerated in combination with fulvestrant or palbociclib in PI3Ka mutant ER + breast cancer PDX model
5. Growth inhibition of helical domain mutant PDX tumors by STX-478
6. STX-478 did not cause metabolic dysfunction in rodents at efficacious doses
7. Chronic dosing of STX-478 (QD*28 days) didn’t cause hyperglycemia in dogs