2. Academic Validation
  3. STX-478, a Mutant-Selective, Allosteric PI3Ka Inhibitor Spares Metabolic Dysfunction and Improves Therapeutic Response in PI3Ka-Mutant Xenografts

STX-478, a Mutant-Selective, Allosteric PI3Ka Inhibitor Spares Metabolic Dysfunction and Improves Therapeutic Response in PI3Ka-Mutant Xenografts

  • Cancer Discov. 2023 Aug 25;CD-23-0396. doi: 10.1158/2159-8290.CD-23-0396.
Leonard Buckbinder 1,  David J St Jean 1,  Trang Tieu 1,  Brendon Ladd 1,  Brendan Hilbert 1,  Weixue Wang 1,  Jacob T Alltucker 1,  Samantha Manimala 1,  Gregory V Kryukov 1,  Natasja Brooijmans 1,  Gregory Dowdell 1,  Philip Jonsson 2,  Michael Huff 1,  Angel Guzman-Perez 1,  Erica L Jackson 3,  Marcus D Goncalves 4,  Darrin D Stuart 1
Affiliations

Affiliations

  • 1 Scorpion Therapeutics (United States), Boston, MA, United States.
  • 2 Loxo Oncology, Boston, United States.
  • 3 Scorpion Therapeutics (United States), United States.
  • 4 Weill Cornell Medicine, New York, NY, United States.
PMID: 37623743 DOI: 10.1158/2159-8290.CD-23-0396
Abstract

Phosphoinositide 3-kinase a (PI3Ka) is one of the most mutated genes across cancers, especially breast, gynecological, and head and neck squamous cell carcinoma tumors. Mutations occur throughout the gene, but hotspot mutations in the helical and kinase domains predominate. The therapeutic benefit of isoform-selective PI3Ka inhibition was established with alpelisib, which displays equipotent activity against the wild-type and mutant Enzyme. Inhibition of wild-type PI3Ka is associated with severe hyperglycemia and rash that limits alpelisib use and suggests that selectively targeting mutant PI3Ka could reduce toxicity and improve efficacy. Here we describe STX-478, an allosteric PI3Ka inhibitor that selectively targets prevalent PI3Ka helical- and kinase-domain mutant tumors. STX-478 demonstrated robust efficacy in human tumor xenografts without causing the metabolic dysfunction observed with alpelisib. Combining STX-478 with fulvestrant and/or cyclin-dependent kinase 4/6 inhibitors was well tolerated and provided robust and durable tumor regression in ER+HER2- xenograft tumor models.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-15244
    99.95%, PI3Kα抑制剂
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