USP7 inhibitors for treating multiple myeloma
Inventors
Buhrlage, Sara • Anderson, Kenneth C. • Chauhan, Dharminder • Dhe-Paganon, Sirano • Liu, Xiaoxi • Seo, Hyuk-Soo
Assignees
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Publication Number
US-12692250-B2
Publication Date
2026-07-28
Expiration Date
Abstract
The present disclosure relates to inhibitors of USP7 useful in the treatment of cancers, and other USP7 mediated diseases, having the Formula: wherein R1, R2, R3, R4, R5, R6, and n are described herein.
Core Innovation
The patent discloses quinazolinone-based Formula I compounds, quinazolinone-piperidine analogs, and pharmaceutically acceptable salts functioning as USP7 inhibitors. Disclosed claims cover a Formula I compound with specified substituents, where n is 0 or 1, and compounds selected from designated depicted structures. Described examples include substituted heteroaromatic cores linked to hydroxypiperidine-containing amide or urea groups, with variation in aromatic and heteroaromatic substituents, linker composition, and stereochemistry.
Evaluations assess USP7 inhibition, DUB selectivity, binding affinity, stability, and cellular effects on HDM2, p53, and p21 protein levels to support p53 pathway modulation. Isothermal titration calorimetry indicates a USP7 Kd of 0.104 μM for compound 10 compared with 7.614 μM for comparator compound A. The compounds are utilized in pharmaceutical compositions and for treating USP7-modulated disorders, particularly cancer and multiple myeloma.
Claims Coverage
The claims define two inventive features across two independent claims covering a Formula I chemical genus and a discrete set of specified chemical structures.
Formula I compound or salt
A compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein R1, R3, and R4 are each H; R2 is halogen; R5 is —OH; R6 is —C(═O)R10 or —C(O)NR7R8; substituents R6–R15 have defined alternatives; and n is 0 or 1.
Compounds selected from specified structures
A compound selected from specified depicted structures, identified by compound numbers 1, 4–9, 18, 20–35, 37, 51–55, 59–62, 66–67, 70–71, 81–82, 85, 87–89, 91–95, 99–100, 107, 119–120, 122, and 125–126.
The independent claims cover the defined Formula I compound genus and a specific set of compounds, with dependent claims reciting pharmaceutical compositions and treatment methods for USP7-modulated diseases or disorders, including cancer.
Stated Advantages
The reported structure-guided optimization of compound 10 produces over 100-fold potency improvement over compound A, and compound 10 shows an approximately 80-fold activity difference from its enantiomer, compound 11.
Compound 10 inhibits the USP7 catalytic domain and full-length USP7 and has a reported binding affinity for USP7.
Documented Applications
Pharmaceutical compositions comprising the disclosed compound or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier.
Treatment of a disease or disorder modulated by USP7, including cancer and multiple myeloma, by administering a compound of the claims or a pharmaceutically acceptable salt thereof to a subject in need thereof.
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