Application of a bivalent "click" approach to target tyrosyl-DNA phosphodiesterase 1 (TDP1).

ABSTRACT: Although inhibiting the DNA repair enzyme tyrosyl-DNA phosphodiesterase 1 (TDP1) synergizes with topoisomerase type I (TOP1) inhibitors in anticancer therapy, development of TDP1 inhibitors has been highly challenging. This may be due to the open and shallow nature of the TDP1 catalytic site and the necessity of competing with a large and highly extended substrate. The toolbox available to chemical biologists for studying TDP1 could be significantly enhanced by introducing the ability to selectively eliminate TDP1 using protein degraders. Our current work starts from phenyl imidazopyridine-based TDP1 inhibitors previously developed from small molecule microarrays (SMMs). Using crystal structures of lead inhibitors bound to TDP1, we designed and synthesized a series of bivalent proteolysis-

SUBMITTER: Zhao XZ 

PROVIDER: S-EPMC11843577 | biostudies-literature | 2025 May

REPOSITORIES: biostudies-literature