Discovery of Isaindigotone Derivatives as Novel Bloom’s Syndrome Protein (BLM) Helicase Inhibitors That Disrupt the BLM/DNA Interactions and Regulate the Homologous Recombination Repair

Homologous
recombination repair (HRR), a crucial approach in DNA damage repair,
is an attractive target in cancer therapy and drug design. The Bloom
syndrome protein (BLM) is a 3′–5′ DNA helicase
that performs an important role in HRR regulation. However, limited
studies about BLM inhibitors and their biological effects have been
reported. Here, we identified a class of isaindigotone derivatives
as novel BLM inhibitors by synthesis, screening, and evaluating. Among
them, compound 29 was found as an effective BLM inhibitor
with a high binding affinity and good inhibitory effect on BLM. Cellular
evaluation indicated that 29 effectively disrupted the
recruitment of BLM at DNA double-strand break sites, promoted an accumulation
of RAD51, and regulated the HRR process. Meanwhile, 29 significantly induced DNA damage responses, as well as apoptosis
and proliferation arrest in cancer cells. Our finding provides a potential
anticancer strategy based on interfering with BLM via small molecules.