Design, Synthesis, and Biological Evaluation of the First Inhibitors of Oncogenic CHD1L

Chromodomain
helicase DNA-binding protein 1 like (CHD1L) is an
oncogene implicated in tumor progression, multidrug resistance, and
metastasis in many types of cancer. In this article, we described
the optimization of the first lead CHD1L inhibitors (CHD1Li) through
drug design and medicinal chemistry. More than 30 CHD1Li were synthesized
and evaluated using a variety of colorectal cancer (CRC) tumor organoid
models and functional assays. The results led to the prioritization
of six lead CHD1Li analogues with improved potency, antitumor activity,
and drug-like properties including metabolic stability and in vivo
pharmacokinetics. Furthermore, lead CHD1Li 6.11 proved
to be an orally bioavailable antitumor agent, significantly reducing
the tumor volume of CRC xenografts generated from isolated quasi mesenchymal
cells (M-phenotype), which possess enhanced tumorigenic properties.
In conclusion, we reported the optimization of first-in-class inhibitors
of oncogenic CHD1L as a novel therapeutic strategy with potential
for the treatment of cancer.