8TGD

STX-478, a Mutant-Selective, Allosteric Inhibitor bound to H1047R PI3Kalpha

Summary for 8TGD

• Entry DOI: 10.2210/pdb8tgd/pdb
• Related: 8TDU
• Descriptor: Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform, Phosphatidylinositol 3-kinase regulatory subunit alpha, 1,2-ETHANEDIOL, ... (6 entities in total)
• Functional Keywords: kinase, inhibitor, transferase, transferase-transferse inhibitor complex, transferase/transferse inhibitor
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 321755.82

Authors

Hilbert, B.,Brooijmans, N.,Buckbinder, L.,St.Jean Jr., D.J. (deposition date: 2023-07-12, release date: 2023-09-06, Last modification date: 2023-11-08)

Primary citation

Buckbinder, L.,St Jean Jr., D.J.,Tieu, T.,Ladd, B.,Hilbert, B.,Wang, W.,Alltucker, J.T.,Manimala, S.,Kryukov, G.V.,Brooijmans, N.,Dowdell, G.,Jonsson, P.,Huff, M.,Guzman-Perez, A.,Jackson, E.L.,Goncalves, M.D.,Stuart, D.D.
STX-478, a Mutant-Selective, Allosteric PI3K alpha Inhibitor Spares Metabolic Dysfunction and Improves Therapeutic Response in PI3K alpha-Mutant Xenografts.
Cancer Discov, 13:2432-2447, 2023

PubMed 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.

PubMed: 37623743
DOI: 10.1158/2159-8290.CD-23-0396

Experimental method

X-RAY DIFFRACTION (2.928 Å)