ArticleCancer discovery2023
STX-478, a Mutant-Selective, Allosteric PI3Kα Inhibitor Spares Metabolic Dysfunction and Improves Therapeutic Response in PI3Kα-Mutant Xenografts.
Article in Cancer discovery, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 45 papers.
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Who cites it
45 citing papers in PubMed, 63 citations in OpenAlex.
- Overall Survival with Inavolisib inThe New England journal of medicine · 2025Trial
- PI3K signaling in breast cancer: therapeutic advances versus adaptive resistance.The Journal of clinical investigation · 2026Review
- PI3Kδ is selectively inhibited by roginolisib by stabilizing the C-terminal helix kα12.Nature communications · 2026Article
- Commentary beyond the ATP site: Cryo-EM views of allosteric PI3KActa pharmaceutica Sinica. B · 2026Article
- Molecular architecture responsible for specific inhibition of oncogenic PI3KActa pharmaceutica Sinica. B · 2026Article
- Contemporary design of small-molecule kinase modulators: orthosteric, allosteric and induced-proximity strategies.Nature reviews. Drug discovery · 2026Review
- A renaissance in targeting the PI3K/AKT/mTOR pathway.Nature reviews. Drug discovery · 2026Review
- Targeting FGFR signaling overcomes therapeutic resistance and immune evasion in oncogenic PIK3CA-driven serous-like endometrial cancer.Nature communications · 2026Article
- Synthesis, structural characterization and molecular docking analysis of novel β-ketoiminato palladium(ii) complexes with anticancer properties.RSC advances · 2026Article
- Review
- Conventional and alternative approaches for targeting PIK3CA and PTEN alterations in head and neck, breast, and other cancers.Advances in biological regulation · 2026Review
- Vascular malformations: from genetics to therapeutics.EMBO molecular medicine · 2026Review
- PI3K/AKT/mTOR axis in vascular malformations: from molecular insights to targeted clinical trials.Orphanet journal of rare diseases · 2025Review
- Structural and allosteric effects of the membrane-bound PI3Kα H1047R mutation and opportunities for drug discovery.Communications chemistry · 2025Article
- Molecular mechanisms of PI3Kα activation by small-molecule activator 1938 and cancer-specific mutation H1047R.Cell discovery · 2025Article
- Kinase signaling cascades: an updated mechanistic landscape.Chemical science · 2025Review
- Multi-node inhibition targeting mTORC1, mTORC2 and PI3Kα potently inhibits the PI3K/AKT/mTOR pathway in endometrial and breast cancer models.British journal of cancer · 2025Article
- Article
- STX-721, a Covalent EGFR/HER2 Exon 20 Inhibitor, Utilizes Exon 20-Mutant Dynamic Protein States and Achieves Unique Mutant Selectivity Across Human Cancer Models.Clinical cancer research : an official journal of the American Association for Cancer Research · 2025Article
- Response and Resistance to RAS Inhibition in Cancer.Cancer discovery · 2025Review
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Authors and funding
17 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
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. Mutations occur throughout the gene, but hotspot mutations in the helical and kinase domains predominate. The therapeutic benefit of isoform-selective PI3Kα inhibition was established with alpelisib, which displays equipotent activity against the wild-type and mutant enzyme. Inhibition of wild-type PI3Kα is associated with severe hyperglycemia and rash, which limits alpelisib use and suggests that selectively targeting mutant PI3Kα could reduce toxicity and improve efficacy. Here we describe STX-478, an allosteric PI3Kα inhibitor that selectively targets prevalent PI3Kα 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. SIGNIFICANCE: These preclinical data demonstrate that the mutant-selective, allosteric PI3Kα inhibitor STX-478 provides robust efficacy while avoiding the metabolic dysfunction associated with the nonselective inhibitor alpelisib. Our results support the ongoing clinical evaluation of STX-478 in PI3Kα-mutated cancers, which is expected to expand the therapeutic window and mitigate counterregulatory insulin release. See related commentary by Kearney and Vasan, p. 2313. This article is featured in Selected Articles from This Issue, p. 2293.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.