INHIBITORS OF HUMAN EZH2, AND METHODS OF USE THEREOF

• Main Authors: KNUTSON, SARAH KATHLEEN, POLLOCK, ROY MACFARLANE, SCOTT, MARGARET DAVIS, COPELAND, ROBERT ALLEN, RICHON, VICTORIA MARIE, KUNTZ, KEVIN WAYNE, SNEERINGER, CHRISTOPHER JOHN
• Format: Patent
• Language: English; French
• Published: 09.04.2024
• Subjects: BEER; BIOCHEMISTRY; CHEMISTRY; COMPOSITIONS OR TEST PAPERS THEREFOR; COMPOSITIONS THEREOF; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL ORENZYMOLOGICAL PROCESSES; CULTURE MEDIA; DERIVATIVES THEREOF; ENZYMOLOGY; HETEROCYCLIC COMPOUNDS; HUMAN NECESSITIES; HYGIENE; INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIRCHEMICAL OR PHYSICAL PROPERTIES; MEASURING; MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEICACIDS OR MICROORGANISMS; MEDICAL OR VETERINARY SCIENCE; METALLURGY; MICROBIOLOGY; MICROORGANISMS OR ENZYMES; MUTATION OR GENETIC ENGINEERING; NUCLEIC ACIDS; NUCLEOSIDES; NUCLEOTIDES; ORGANIC CHEMISTRY; PHYSICS; PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES; PROCESSES OF PREPARING SUCH COMPOSITIONS; PROPAGATING, PRESERVING OR MAINTAINING MICROORGANISMS; SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS ORMEDICINAL PREPARATIONS; SPIRITS; SUGARS; TESTING; VINEGAR; WINE

The invention relates to inhibition of wild-type and certain mutant forms of human histone methyltransferase EZH2, the catalytic subunit of the PRC2 complex which catalyzes the mono- through tri-methylation of lysine 27 on histone H3 (H3-K27). In one embodiment the inhibition is selective for the mutant form of the EZH2, such that trimethylation of H3- K27, which is associated with certain cancers, is inhibited. The methods can be used to treat cancers including follicular lymphoma and diffuse large B-cell lymphoma (DLBCL). Also provided are methods for identifying small molecule selective inhibitors of the mutant forms of EZH2 and also methods for determining responsiveness to an EZH2 inhibitor in a subject. Cette invention concerne l'inhibition des formes type sauvage et de certaines formes mutantes de l'histone méthyltransférase humaine EZH2, le sous-motif catalytique du complexe PRC2 qui catalyse de la monométhylation à la triméthylation de la lysine 27 sur l'histone H3 (H3-K27). Dans un mode de réalisation, l'inhibition est sélective pour la forme mutante de l'EZH2, de sorte que la triméthylation d'H3-K27, qui est associée à certains cancers, est inhibée. Les méthodes ci-décrites peuvent être utilisées pour traiter les cancers comprenant le lymphome folliculaire et le lymphome diffus à grosses cellules B (DLBCL). Des procédés permettant d'identifier des inhibiteurs sélectifs à petites molécules des formes mutantes d'EZH2 et des procédés pour déterminer la réactivité à un inhibiteur d'EZH2 chez un sujet sont également décrits.