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Design, Synthesis, and Biological Evaluation of the First Inhibitors of Oncogenic CHD1L.
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.
Afiliación
  • Prigaro BJ; The Skaggs School of Pharmacy and Pharmaceutical Sciences, Department of Pharmaceutical Sciences, The CU Cancer Center, Aurora, Colorado 80045, United States.
  • Esquer H; The Skaggs School of Pharmacy and Pharmaceutical Sciences, Department of Pharmaceutical Sciences, The CU Cancer Center, Aurora, Colorado 80045, United States.
  • Zhou Q; The Skaggs School of Pharmacy and Pharmaceutical Sciences, Department of Pharmaceutical Sciences, The CU Cancer Center, Aurora, Colorado 80045, United States.
  • Pike LA; The Skaggs School of Pharmacy and Pharmaceutical Sciences, Department of Pharmaceutical Sciences, The CU Cancer Center, Aurora, Colorado 80045, United States.
  • Awolade P; The Skaggs School of Pharmacy and Pharmaceutical Sciences, Department of Pharmaceutical Sciences, The CU Cancer Center, Aurora, Colorado 80045, United States.
  • Lai XH; The Skaggs School of Pharmacy and Pharmaceutical Sciences, Department of Pharmaceutical Sciences, The CU Cancer Center, Aurora, Colorado 80045, United States.
  • Abraham AD; The Skaggs School of Pharmacy and Pharmaceutical Sciences, Department of Pharmaceutical Sciences, The CU Cancer Center, Aurora, Colorado 80045, United States.
  • Abbott JM; The Skaggs School of Pharmacy and Pharmaceutical Sciences, Department of Pharmaceutical Sciences, The CU Cancer Center, Aurora, Colorado 80045, United States.
  • Matter B; The Skaggs School of Pharmacy and Pharmaceutical Sciences, Department of Pharmaceutical Sciences, The CU Cancer Center, Aurora, Colorado 80045, United States.
  • Kompella UB; The Skaggs School of Pharmacy and Pharmaceutical Sciences, Department of Pharmaceutical Sciences, The CU Cancer Center, Aurora, Colorado 80045, United States.
  • Messersmith WA; The University of Colorado (CU) Anschutz Medical Campus (AMC) Center for Drug Discovery, The CU Cancer Center, Aurora, Colorado 80045, United States.
  • Gustafson DL; The School of Medicine, Division of Medical Oncology, The CU Cancer Center, Aurora, Colorado 80045, United States.
  • LaBarbera DV; The University of Colorado (CU) Anschutz Medical Campus (AMC) Center for Drug Discovery, The CU Cancer Center, Aurora, Colorado 80045, United States.
J Med Chem ; 65(5): 3943-3961, 2022 03 10.
Article en En | MEDLINE | ID: mdl-35192363
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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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: ADN Helicasas / Proteínas de Unión al ADN / Antineoplásicos Límite: Humans Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2022 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: ADN Helicasas / Proteínas de Unión al ADN / Antineoplásicos Límite: Humans Idioma: En Revista: J Med Chem Asunto de la revista: QUIMICA Año: 2022 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos