Design, Synthesis, and Biological Evaluation of the First Inhibitors of Oncogenic CHD1L.
Brett J PrigaroHector EsquerQiong ZhouLaura A PikePaul AwoladeXin-He LaiAdedoyin D AbrahamJoshua M AbbottBrock MatterUday B KompellaWells A MessersmithDaniel L GustafsonDaniel V LaBarberaPublished in: Journal of medicinal chemistry (2022)
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.
Keyphrases
- binding protein
- papillary thyroid
- ion batteries
- transcription factor
- induced apoptosis
- poor prognosis
- bone marrow
- emergency department
- molecular docking
- cell proliferation
- cell cycle arrest
- lymph node metastasis
- childhood cancer
- climate change
- circulating tumor cells
- endoplasmic reticulum stress
- pi k akt
- smoking cessation