Our invention relates to novel triazine compounds, containing chemical reactive groups (warheads) and behaving as reversible and irreversible covalent inhibitors. Linkers have been introduced to target a solvent exposed, distal cysteine at > 10 A from the core reversible inhibitor. Different exit vectors have been investigated to modulate inhibitor intrinsic reactivity and efficiency in covalent bond formation. We disclose novel, optimized covalent modifiers of phosphoinositide 3-kinase alpha (PI3Ka), an enzyme frequently altered in human malignancies. The compounds of the invention could be exploited as therapeutic agents and chemical probes useful for the investigation of the role of PI3K isoforms in cancer and metabolism, and for treatment of PI3Ka-driven cancers and malformations.
TRIAZINE DERIVATIVE AS REVERSIBLE AND IRREVERSIBLE COVALENT INHIBITORS OF PI3K / C. Borsari, M. Wymann.
TRIAZINE DERIVATIVE AS REVERSIBLE AND IRREVERSIBLE COVALENT INHIBITORS OF PI3K
C. Borsari;
2022
Abstract
Our invention relates to novel triazine compounds, containing chemical reactive groups (warheads) and behaving as reversible and irreversible covalent inhibitors. Linkers have been introduced to target a solvent exposed, distal cysteine at > 10 A from the core reversible inhibitor. Different exit vectors have been investigated to modulate inhibitor intrinsic reactivity and efficiency in covalent bond formation. We disclose novel, optimized covalent modifiers of phosphoinositide 3-kinase alpha (PI3Ka), an enzyme frequently altered in human malignancies. The compounds of the invention could be exploited as therapeutic agents and chemical probes useful for the investigation of the role of PI3K isoforms in cancer and metabolism, and for treatment of PI3Ka-driven cancers and malformations.
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