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.
Subject(s)
Antineoplastic Agents , DNA Helicases , DNA-Binding Proteins , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Carcinogenesis/genetics , Cell Line, Tumor , DNA Helicases/antagonists & inhibitors , DNA-Binding Proteins/antagonists & inhibitors , Drug Design , Humans , OncogenesABSTRACT
Metformin is considered to be one of the most effective therapeutics for treating type 2 diabetes because it specifically reduces hepatic gluconeogenesis without increasing insulin secretion, inducing weight gain or posing a risk of hypoglycaemia. For over half a century, this agent has been prescribed to patients with type 2 diabetes worldwide, yet the underlying mechanism by which metformin inhibits hepatic gluconeogenesis remains unknown. Here we show that metformin non-competitively inhibits the redox shuttle enzyme mitochondrial glycerophosphate dehydrogenase, resulting in an altered hepatocellular redox state, reduced conversion of lactate and glycerol to glucose, and decreased hepatic gluconeogenesis. Acute and chronic low-dose metformin treatment effectively reduced endogenous glucose production, while increasing cytosolic redox and decreasing mitochondrial redox states. Antisense oligonucleotide knockdown of hepatic mitochondrial glycerophosphate dehydrogenase in rats resulted in a phenotype akin to chronic metformin treatment, and abrogated metformin-mediated increases in cytosolic redox state, decreases in plasma glucose concentrations, and inhibition of endogenous glucose production. These findings were replicated in whole-body mitochondrial glycerophosphate dehydrogenase knockout mice. These results have significant implications for understanding the mechanism of metformin's blood glucose lowering effects and provide a new therapeutic target for type 2 diabetes.
Subject(s)
Gluconeogenesis/drug effects , Glycerolphosphate Dehydrogenase/antagonists & inhibitors , Metformin/pharmacology , Mitochondria/enzymology , Animals , Blood Glucose/analysis , Blood Glucose/biosynthesis , Cells, Cultured , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/enzymology , Diabetes Mellitus, Type 2/metabolism , Glycerolphosphate Dehydrogenase/deficiency , Glycerolphosphate Dehydrogenase/genetics , Glycerolphosphate Dehydrogenase/metabolism , Humans , Hypoglycemic Agents/pharmacology , Insulin/metabolism , Insulin Secretion , Lactic Acid/metabolism , Liver/drug effects , Liver/metabolism , Male , Mice, Knockout , Oxidation-Reduction/drug effects , Rats , Rats, Sprague-DawleyABSTRACT
Herboxidiene is a natural product that has previously been shown to exhibit antitumor activity by targeting the spliceosome. This activity makes herboxidiene a valuable starting point for the development of anticancer drugs. Here, we report an improved enantioselective synthesis of herboxidiene and the first report of its biologically active totally synthetic analog: 6-norherboxidiene. The synthesis of the tetrahydropyran moiety utilizes the novel application of inverse electron-demand Diels-Alder chemistry and the Ferrier-type rearrangement as key steps. We report, for the first time, cytotoxicity IC50s for synthetic herboxidiene and analogs in human tumor cell lines. We have also demonstrated that synthetic herboxidiene and its analogs can potently modulate the alternate splicing of MDM-2 pre-mRNA.
Subject(s)
Alternative Splicing , Antineoplastic Agents/chemical synthesis , Drug Design , Epoxy Compounds/chemical synthesis , Fatty Alcohols/chemical synthesis , Macrolides/chemical synthesis , Pyrans/chemical synthesis , RNA Precursors/genetics , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Cell Survival/drug effects , Cycloaddition Reaction , Epoxy Compounds/chemistry , Epoxy Compounds/pharmacology , Fatty Alcohols/chemistry , Fatty Alcohols/pharmacology , Humans , Inhibitory Concentration 50 , Macrolides/chemistry , Macrolides/pharmacology , Models, Molecular , Molecular Structure , Proto-Oncogene Proteins c-mdm2/genetics , Pyrans/chemistry , Pyrans/pharmacologyABSTRACT
Ten new beta-D-ribofuranosyl and 2'-beta-C-methyl-beta-D-ribofuranosyl triciribine derivatives 4-13 with various N4 and 6-N substituents on the tricyclic ring were synthesized from the corresponding toyocamycin and new 2'-beta-C-methyl toyocamycin derivatives. The inhibitory studies of these compounds in the HCV replicon assay reveal that some of them possess interesting anti-HCV properties with low cytotoxicity.
