2. Academic Validation
  3. Design, Synthesis, and Biological Evaluation of the First Inhibitors of Oncogenic CHD1L

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

  • J Med Chem. 2022 Mar 10;65(5):3943-3961. doi: 10.1021/acs.jmedchem.1c01778.
Brett J Prigaro 1,  Hector Esquer 1,  Qiong Zhou 1,  Laura A Pike 1,  Paul Awolade 1,  Xin-He Lai 1,  Adedoyin D Abraham 1,  Joshua M Abbott 1,  Brock Matter 1,  Uday B Kompella 1 2,  Wells A Messersmith 3 2 4,  Daniel L Gustafson 5 2 4,  Daniel V LaBarbera 1 2 4
Affiliations

Affiliations

  • 1 The Skaggs School of Pharmacy and Pharmaceutical Sciences, Department of Pharmaceutical Sciences, The CU Cancer Center, Aurora, Colorado 80045, United States.
  • 2 The University of Colorado (CU) Anschutz Medical Campus (AMC) Center for Drug Discovery, The CU Cancer Center, Aurora, Colorado 80045, United States.
  • 3 The School of Medicine, Division of Medical Oncology, The CU Cancer Center, Aurora, Colorado 80045, United States.
  • 4 The CU Cancer Center, Aurora, Colorado 80045, United States.
  • 5 Flint Animal Cancer Center and Department of Clinical Sciences, School of Biomedical Engineering, Colorado State University, Fort Collins, Colorado 80523, United States.
PMID: 35192363 DOI: 10.1021/acs.jmedchem.1c01778
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.

Figures
Products