University of Delaware

The United States of America, as Represented by the Secretary, Department of Health and Human Services

Zhihao Zhuang

Anton Simeonov

David Joseph Maloney

Ajit Jadhav

Diane K Luci

Thomas S Dexheimer

Guorui Li

Andrew S Rosenthal

Qin Liang

Disclosed are inhibitors of the USP1/UAF1 deubiquitinase complex, for example. of formula (I), wherein R, R, and Q are as defined herein, which are useful in treating diseases such as cancer, and improving the efficacy of DNA damaging agents in cancer treatment. Also disclosed is a composition comprising a pharmaceutically suitable carrier and at least one compound of the invention, a method of method of inhibiting a heterodimeric deubiquitinase complex in a cell, and a method of enhancing the chemotherapeutic treatment of cancer in a mammal undergoing treatment with an anti cancer agent. Further disclosed is a method of preparing compounds of the invention.

Inhibitors of the USP1/UAF1 deubiquitinase complex and uses thereof

Deubiquitinating enzyme (DUB) probes are provided that resemble native diubiquitin (diUB) with a similar linkage size and that may contain a Michael acceptor for trapping the DUB active-site cysteine. For example, both K63- and K48-linked diubiquitin probes are generated using a facile chemical ligation method, utilizing the linker compound 3-(2-(bromomethyl)-1,3-dioxolan-2-yl)prop-2-en-1-amine. The diUb probes are capable of labelling DUBs from different families and may be employed to reveal intrinsic linkage specificities of DUBs.

Method of generating linkage-specific di-and polyprotein probes

Growing community of inventors

Wilmington, DE, United States of America

Zhihao Zhuang