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

Abstract

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.

The validation of new CHD1L inhibitors as a therapeutic strategy for cancer

“…The catalytic enzyme assay was performed as previously described [ 24 , 27 ]. A reaction mixture was prepared at the concentrations of 100 nM of the catalytic domain of CHD1L (cat-CHD1L) and 200 nM/L of c-Myc DNA or mononucleosome (Active Motif, Ref#: 81770) in buffer (50 mM Tris pH 7.5, 50 mM NaCl, 1 mM DTT, 5% glycerol).…”

“…The CHD1Li were tested at seven different concentrations to determine their cytotoxic effect on tumor organoids as previously described [ 24 , 27 ]. Compounds were dissolved in DMSO (Sigma-Aldrich, Ref #34869) to make a 10 mM stock solution and stored at − 80°C.…”

“…The EMT dual reporter assay was performed as previously described [ 24 , 26 , 27 ]. SW620-GFP+ cells were plated as 3D organoids and treated with 0–40 μM of CHD1Li as described above.…”

“…MD simulation was conducted as previously described [ 25 ]. Briefly, the requisite model systems for CHD1Li 9 and 11 were created using the system builder.…”

“…Recently, we reported the high-throughput screening (HTS) discovery and pre-clinical development of the first-in-class CHD1Li for the treatment of cancer, exemplified by the pyrimidine-based lead drug OTI-611 ( aka 6.11) [ 24 , 25 ]. The first generation CHD1Li display potent antitumor activity through allosteric inhibition of CHD1L ATPase, which induces programmed cell death.…”