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 Å 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 (PI3Kα), 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 PI3Kα-driven cancers and malformations.

TRIAZINE DERIVATIVE AS REVERSIBLE AND IRREVERSIBLE COVALENT INHIBITORS OF PI3K | [TRIAZINDERIVAT ALS REVERSIBLE UND IRREVERSIBLE KOVALENTE PI3K-HEMMER] / C. Borsari, M. Wymann.

TRIAZINE DERIVATIVE AS REVERSIBLE AND IRREVERSIBLE COVALENT INHIBITORS OF PI3K | [TRIAZINDERIVAT ALS REVERSIBLE UND IRREVERSIBLE KOVALENTE PI3K-HEMMER]

C. Borsari;
2024

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 Å 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 (PI3Kα), 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 PI3Kα-driven cancers and malformations.
Universität Basel
EP4320115 (A1)
EP20220721777 20220409
14-feb-2024
Settore CHIM/08 - Chimica Farmaceutica
https://worldwide.espacenet.com/publicationDetails/biblio?CC=EP&NR=4320115&KC=&FT=E&locale=en_EP#
TRIAZINE DERIVATIVE AS REVERSIBLE AND IRREVERSIBLE COVALENT INHIBITORS OF PI3K | [TRIAZINDERIVAT ALS REVERSIBLE UND IRREVERSIBLE KOVALENTE PI3K-HEMMER] / C. Borsari, M. Wymann.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/1070249
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