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TitleMolecular architecture responsible for specific inhibition of oncogenic PI3K mutants by RLY-2608 and STX-478.
Journal, issue, pagesActa Pharm Sin B, Vol. 16, Issue 9, Page 5884-5900, Year 2026
Publish dateJul 5, 2026
AuthorsXiao Liu / Yanyan Chen / Guanyi Li / Anqi Chen / Qingtong Zhou / Ming-Wei Wang /
PubMed AbstractHotspot mutations in phosphoinositide 3-kinase alpha (PI3K), such as H1047R, E542K, and E545K, drive tumorigenesis across multiple cancer types. Orthosteric PI3K inhibitors are effective but have ...Hotspot mutations in phosphoinositide 3-kinase alpha (PI3K), such as H1047R, E542K, and E545K, drive tumorigenesis across multiple cancer types. Orthosteric PI3K inhibitors are effective but have toxicity against wild-type PI3K, the emergence of resistance, and a narrow therapeutic index. Allosteric inhibitors such as RLY-2608 and STX-478 offer a promising path toward mutant-specific suppression, yet the structural basis for their selectivity and mechanisms of action remain elusive. Here, we report high-resolution cryogenic electron microscopy structures of RLY-2608- and STX-478-bound H1047R, E542K, and E545K, revealing a shared cryptic allosteric pocket, accessible only through a major conformational rearrangement of the activation loop that is stabilized in oncogenic mutants. While both inhibitors occupy this pocket, they have distinct interaction networks and propagate divergent allosteric activities: RLY-2608 induces large-scale remodeling of catalytic and membrane-interacting elements, whereas STX-478 reinforces autoinhibitory interfaces between p110 and p85 subunits. Comparative analysis provides structural insights into their differentiated potency and selectivity.
External linksActa Pharm Sin B / PubMed:42764855 / PubMed Central
MethodsEM (single particle)
Resolution2.86 - 3.31 Å
Structure data

67325

9xw5

EMDB-67325, PDB-9xw5:
Cryo-EM structure of PI3Kalpha H1047R mutation in complex with STX-478
Method: EM (single particle) / Resolution: 3.31 Å

67327

9xw7

EMDB-67327, PDB-9xw7:
Cryo-EM structure of PI3Kalpha E545K mutation in complex with STX-478
Method: EM (single particle) / Resolution: 3.01 Å

67328

9xw8

EMDB-67328, PDB-9xw8:
Cryo-EM structure of PI3Kalpha E542K mutation in complex with STX-478
Method: EM (single particle) / Resolution: 2.86 Å

Chemicals

ChemComp-ZWE:
N-(2-aminopyrimidin-5-yl)-N'-[(1R)-1-(5,7-difluoro-3-methyl-1-benzofuran-2-yl)-2,2,2-trifluoroethyl]urea

ChemComp-HOH:
WATER

Source
  • homo sapiens (human)
KeywordsSTRUCTURAL PROTEIN / Phosphoinositide 3-kinase / drug target / ligand / binding pocket / hotspot mutation / allosteric inhbitor

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