jm0c00917_si_001.pdf (9.46 MB)
Design, Synthesis, and Evaluation of New Quinazolinone Derivatives that Inhibit Bloom Syndrome Protein (BLM) Helicase, Trigger DNA Damage at the Telomere Region, and Synergize with PARP Inhibitors
journal contribution
posted on 2020-08-07, 13:04 authored by Chen-Xi Wang, Zi-Lin Zhang, Qi-Kun Yin, Jia-Li Tu, Jia-En Wang, Yao-Hao Xu, Yong Rao, Tian-Miao Ou, Shi-Liang Huang, Ding Li, Hong-Gen Wang, Qing-Jiang Li, Jia-Heng Tan, Shuo-Bin Chen, Zhi-Shu HuangDNA damage response
(DDR) pathways are crucial for the survival
of cancer cells and are attractive targets for cancer therapy. Bloom
syndrome protein (BLM) is a DNA helicase that performs important roles
in DDR pathways. Our previous study discovered an effective new BLM
inhibitor with a quinazolinone scaffold by a screening assay. Herein,
to better understand the structure–activity relationship (SAR)
and biological roles of the BLM inhibitor, a series of new derivatives
were designed, synthesized, and evaluated based on this scaffold.
Among them, compound 9h exhibited nanomolar inhibitory
activity and binding affinity for BLM. 9h could effectively
disrupt BLM recruitment to DNA in cells. Furthermore, 9h inhibited the proliferation of the colorectal cell line HCT116 by
significantly triggering DNA damage in the telomere region and inducing
apoptosis, especially in combination with a poly (ADP-ribose) polymerase
(PARP) inhibitor. This result suggested a synthetic lethal effect
between the BLM and PARP inhibitors in DDR pathways.