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PI3Kdelta is selectively inhibited by roginolisib through stabilizing of the C-terminal helix ka12

ABSTRACT: Phosphoinositide 3-kinases (PI3Ks) are major regulators of cell growth, proliferation and signalling, constituting key therapeutic targets in cancer, inflammation, and other diseases. Individual class I PI3K isoforms control non-redundant cellular functions, imposing the need to generate isoform-specific inhibition for therapeutic intervention. Roginolisib is a selective PI3Kδ inhibitor that shows great promises for the treatment of cancer. Using a combination of X-ray crystallography, molecular dynamics simulations, and hydrogen-deuterium exchange mass spectrometry, we have uncovered the mechanism driving potent and isoform-selective inhibition of PI3Kδ. Upon occupying the ATP binding site, roginolisib uniquely stabilises the catalytic C-terminal helix kα12, hereby locking the enzyme in an inactive conformation and interfering with membrane targeting of PI3Kδ. This binding mode also results in more sustained inhibition of PIP3 formation in CLL patient samples. We thus uncovered a distinct new mode of PI3K inhibition that is anticipated to inform the rational design of next-generation, more selective and effective pharmacological strategies.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Oscar Vadas

LAB HEAD: Oscar Vadas

PROVIDER: PXD071872 | Pride | 2026-06-24

REPOSITORIES: Pride

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			Action	DRS
	20241003_OT_HDXMS_08.mgf	Mgf
	20241003_OT_HDXMS_08.raw	Raw
	20241003_OT_HDXMS_100.raw	Raw
	20241003_OT_HDXMS_101.raw	Raw
	20241003_OT_HDXMS_102.raw	Raw

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