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 chemistr...

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Published inJournal of medicinal chemistry Vol. 65; no. 5; pp. 3943 - 3961
Main Authors Prigaro, Brett J, Esquer, Hector, Zhou, Qiong, Pike, Laura A, Awolade, Paul, Lai, Xin-He, Abraham, Adedoyin D, Abbott, Joshua M, Matter, Brock, Kompella, Uday B, Messersmith, Wells A, Gustafson, Daniel L, LaBarbera, Daniel V
Format Journal Article
LanguageEnglish
Published United States American Chemical Society 10.03.2022
Subjects
Antineoplastic Agents - pharmacology
Antineoplastic Agents - therapeutic use
Carcinogenesis - genetics
Cell Line, Tumor
DNA Helicases - antagonists & inhibitors
DNA-Binding Proteins - antagonists & inhibitors
Drug Design
Humans
Oncogenes
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Summary: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.
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X.L. Conducted cat-CHD1L recombinant enzyme purification.
W.A.M. Provided CRC patient samples and contributed patient sample protocols.
L.A.P. Co-designed and conducted animal studies and data analysis.
D.L.G. Co-designed and conducted animal PK study design, data acquisition and analysis.
B.M. Co-designed and conducted microsomal stability LCMS analysis.
D.V.L. Conceived, wrote, and edited the paper, and conducted all experimental design and data analysis.
P.A. Co-designed and conducted molecular modeling and data analysis and contributed to manuscript writing.
U.B.K. Co-designed microsomal stability LCMS and analysis and contributed to manuscript editing.
B.J.P. Co-designed and conducted chemical syntheses, compound analysis, and contributed to manuscript writing.
J.M.A. Contributed to cat-CHD1L purification.
H.E. Co-designed and conducted biological experiments, data analysis, and contributed to manuscript writing
Q.Z. Co-designed and conducted biological experiments and data analysis.
A.D.A. Contributed to compound synthesis.
B.J.P. and H.E. contributed equally.
Author Contributions
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.1c01778