Design, Synthesis, and Biological Evaluation of the First Inhibitors of Oncogenic CHD1L
| Autor: | Brett J. Prigaro, Hector Esquer, Qiong Zhou, Laura A. Pike, Paul Awolade, Xin-He Lai, Adedoyin D. Abraham, Joshua M. Abbott, Brock Matter, Uday B. Kompella, Wells A. Messersmith, Daniel L. Gustafson, Daniel V. LaBarbera |
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| Rok vydání: | 2022 |
| Předmět: | |
| Zdroj: | J Med Chem |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | 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 describe the optimization of the first lead CHD1L inhibitors (CHD1Li) through drug design and medicinal chemistry. More than thirty 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 analogs with improved potency and antitumor activity, and drug-like properties including metabolic stability and in vivo pharmacokinetics. Furthermore, lead CHD1Li 6.11 proved to be an oral 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 report the optimization of first-in-class inhibitors of oncogenic CHD1L as a novel therapeutic strategy with potential for the treatment of cancer. |
| Databáze: | OpenAIRE |
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