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1.
Mol Cancer Ther ; 22(1): 25-36, 2023 01 03.
Article in English | MEDLINE | ID: mdl-36302395

ABSTRACT

We have synthesized an oxetane derivative of the benzimidazole compound mebendazole (OBD9) with enhanced solubility and strong anticancer activity in multiple types of cancer cells, especially colorectal cancer. In this report, we provide evidence that OBD9 suppresses colorectal cancer growth by interfering with the Wnt signaling pathway, a main driver of cell growth in colorectal cancer. Specifically, we find that OBD9 induces autophagic degradation of TNIK (traf2 and Nck-interacting kinase), which promotes T-cell factor-4 (TCF4)/beta-catenin-mediated gene expression. Thus, OBD9 as a TNIK inhibitor blocks Wnt/beta-catenin signaling at the final step of transcriptional activation. We suggest that OBD9 provides a potential novel autophagy-mediated, Wnt-damping therapeutic strategy for the treatment of colorectal cancer.


Subject(s)
Colonic Neoplasms , Colorectal Neoplasms , Humans , Wnt Signaling Pathway , beta Catenin/metabolism , Cell Line, Tumor , Colonic Neoplasms/drug therapy , Colorectal Neoplasms/drug therapy
2.
Sci Adv ; 6(3): eaay8230, 2020 01.
Article in English | MEDLINE | ID: mdl-31998845

ABSTRACT

Aryl hydrocarbon receptor (AHR) is an essential regulator of gut immunity and a promising therapeutic target for inflammatory bowel disease (IBD). Current AHR agonists are inadequate for clinical translation due to low activity, inadequate pharmacokinetics, or toxicity. We synthesized a structurally diverse library and used integrated computational and experimental studies to discover mechanisms governing ligand-receptor interaction and to design potent drug leads PY109 and PY108, which display physiochemical drug-likeness properties, desirable pharmacokinetic profiles, and low toxicity. In a murine model of dextran sulfate sodium-induced colitis, orally administered compounds increase interleukin-22 (IL-22) production and accelerate mucosal healing by modulating mucosal adaptive and innate lymphoid cells. AHR and IL-22 pathway induction was confirmed using RNA sequencing and characterization of the lymphocyte protein-protein interaction network. Significant induction of IL-22 was also observed using human T cells from patients with IBD. Our findings support rationally designed AHR agonists for IBD therapy.


Subject(s)
Drug Design , Immunomodulation/drug effects , Lymphocytes/drug effects , Lymphocytes/metabolism , Receptors, Aryl Hydrocarbon/agonists , Wound Healing/drug effects , Wound Healing/immunology , Animals , Antimicrobial Cationic Peptides/genetics , Antimicrobial Cationic Peptides/pharmacology , Colitis/etiology , Colitis/metabolism , Colitis/pathology , Dextran Sulfate/adverse effects , Disease Models, Animal , Drug Stability , Gene Expression , Humans , Interleukins/biosynthesis , Intestinal Mucosa/drug effects , Intestinal Mucosa/immunology , Intestinal Mucosa/metabolism , Intestinal Mucosa/pathology , Ligands , Lymphocytes/immunology , Mice , Models, Molecular , Molecular Conformation , Receptors, Aryl Hydrocarbon/chemistry , Regeneration , Structure-Activity Relationship , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , Wound Healing/genetics , Interleukin-22
3.
J Invest Dermatol ; 140(4): 901-911.e11, 2020 04.
Article in English | MEDLINE | ID: mdl-31568772

ABSTRACT

Impaired wound healing in the diabetic foot is a major problem often leading to amputation. Mast cells have been shown to regulate wound healing in diabetes. We developed an indole-carboxamide type mast cell stabilizer, MCS-01, which proved to be an effective mast cell degranulation inhibitor in vitro and can be delivered topically for prolonged periods through controlled release by specifically designed alginate bandages. In diabetic mice, both pre- and post-wounding, topical MCS-01 application accelerated wound healing comparable to that achieved with systemic mast cell stabilization. Moreover, MCS-01 altered the macrophage phenotype, promoting classically activated polarization. Bulk transcriptome analysis from wounds treated with MCS-01 or placebo showed that MCS-01 significantly modulated the mRNA and microRNA profile of diabetic wounds, stimulated upregulation of pathways linked to acute inflammation and immune cell migration, and activated the NF-κB complex along with other master regulators of inflammation. Single-cell RNA sequencing analysis of 6,154 cells from wounded and unwounded mouse skin revealed that MCS-01 primarily altered the gene expression of mast cells, monocytes, and keratinocytes. Taken together, these findings offer insights into the process of diabetic wound healing and suggest topical mast cell stabilization as a potentially successful treatment for diabetic foot ulceration.


Subject(s)
Diabetes Mellitus, Experimental/therapy , Diabetic Foot/drug therapy , Immunity, Cellular , Indoles/pharmacology , Skin/metabolism , Wound Healing/drug effects , Animals , Cell Movement , Diabetes Mellitus, Experimental/metabolism , Diabetes Mellitus, Experimental/pathology , Diabetic Foot/metabolism , Diabetic Foot/pathology , Keratinocytes/drug effects , Keratinocytes/metabolism , Keratinocytes/pathology , Mast Cells/metabolism , Mice , Skin/drug effects , Skin/pathology , Wound Healing/immunology
4.
Expert Opin Ther Pat ; 28(4): 317-330, 2018 04.
Article in English | MEDLINE | ID: mdl-29473428

ABSTRACT

INTRODUCTION: Indoleamine 2,3-dioxygenase 1 (IDO1) is overexpressed by cancer cells and the antigen presenting dendritic cells in the tumor microenvironment (TME). Activation of IDO1 depletes tryptophan and produces kynurenine, which induces T cell anergy and suppresses tumor control by the immune system. When combined with an immune checkpoint inhibitor, IDO1 inhibitors have shown promising anticancer activity in preclinical tumor models as well as in early stage clinical trials. AREAS COVERED: IDO1 inhibitors disclosed in the patent literature from 2013-2017 are categorized, when applicable, according to their structural similarity to the clinical development candidates indoximod and PF-06840003, navoximod, epacadostat, KHK2455 and aryl-1,2-diamines, and BMS-986205 among others, respectively. Representative structures and their IDO1 inhibitory activity are presented to highlight the novelty and activity. Finally, the reported cocrystal structures were analyzed to provide insights for inhibitor-enzyme interactions and guidance for the design and discovery of next generation inhibitors. EXPERT OPINION: This review demonstrates that the structural diversity of new IDO1 inhibitors could be expanded via a number of approaches.


Subject(s)
Antineoplastic Agents/pharmacology , Indoleamine-Pyrrole 2,3,-Dioxygenase/antagonists & inhibitors , Neoplasms/drug therapy , Animals , Drug Design , Drug Discovery/methods , Enzyme Inhibitors/pharmacology , Humans , Neoplasms/enzymology , Patents as Topic
5.
Eur J Med Chem ; 144: 372-385, 2018 Jan 20.
Article in English | MEDLINE | ID: mdl-29288939

ABSTRACT

Metastases account for more than 90% of all cancer deaths and respond poorly to most therapies. There remains an urgent need for new therapeutic modalities for the treatment of advanced metastatic cancers. The benzimidazole methylcarbamate drugs, commonly used as anti-helmitics, have been suggested to have anticancer activity, but progress has been stalled by their poor water solubility and poor suitability for systemic delivery to disseminated cancers. We synthesized and characterized the anticancer activity of novel benzimidazoles containing an oxetane or an amine group to enhance solubility. Among them, the novel oxetanyl substituted compound 18 demonstrated significant cytotoxicity toward a variety of cancer cell types including prostate, lung, and ovarian cancers with strong activity toward highly aggressive cancer lines (IC50: 0.9-3.8 µM). Compound 18 achieved aqueous solubility of 361 µM. In a mouse xenograft model of a highly metastatic human prostate cancer, compound 18 (30 mg/kg) significantly inhibited the growth of established tumors (T/C: 0.36) without noticeable toxicity.


Subject(s)
Antineoplastic Agents/pharmacology , Benzimidazoles/pharmacology , Carbamates/pharmacology , Water/chemistry , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Benzimidazoles/chemical synthesis , Benzimidazoles/chemistry , Carbamates/chemical synthesis , Carbamates/chemistry , Cell Proliferation/drug effects , Cell Survival/drug effects , Dose-Response Relationship, Drug , Humans , Male , Mice , Molecular Docking Simulation , Molecular Structure , Neoplasms, Experimental/drug therapy , Neoplasms, Experimental/pathology , Solubility , Structure-Activity Relationship , Tumor Cells, Cultured
6.
Trends Pharmacol Sci ; 39(3): 307-325, 2018 03.
Article in English | MEDLINE | ID: mdl-29254698

ABSTRACT

Indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase 2 (TDO2) catalyze the commitment step of the kynurenine (KYN) metabolic pathway. Traditionally the immunosuppressive effect of IDO1 has been attributed mainly to reduced levels of tryptophan, which activates the kinase general control nonderepressible 2 (GCN2). Emerging data have shed light on an unexpected role of the ligand-activated transcription factor aryl hydrocarbon receptor (AhR) in transducing the tumor immune escape function imparted by IDO1 and TDO2. AhR activation by the IDO1/TDO2 product KYN leads to the generation of immune-tolerant dendritic cells (DCs) and regulatory T cells, which collectively foster a tumor immunological microenvironment that is defective in recognizing and eradicating cancer cells. Multiple IDO1 inhibitors have been evaluated in clinical trials. There are novel modalities downstream of IDO1/TDO2 for pharmacological interventions. We review recent progress and future perspectives in targeting the IDO1/TDO2-KYN-AhR signaling pathway for the development of novel cancer immunotherapies.


Subject(s)
Antineoplastic Agents/therapeutic use , Immunosuppressive Agents/therapeutic use , Immunotherapy/methods , Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism , Kynurenine/metabolism , Neoplasms/drug therapy , Receptors, Aryl Hydrocarbon/metabolism , Tryptophan Oxygenase/metabolism , Animals , Antineoplastic Agents/pharmacology , Humans , Immunosuppressive Agents/pharmacology , Indoleamine-Pyrrole 2,3,-Dioxygenase/antagonists & inhibitors , Neoplasms/therapy , Receptors, Aryl Hydrocarbon/drug effects , Tryptophan Oxygenase/antagonists & inhibitors
7.
Free Radic Biol Med ; 50(8): 918-25, 2011 Apr 15.
Article in English | MEDLINE | ID: mdl-20977937

ABSTRACT

It is well known that antioxidants have protective effects against oxidative stress. Unfortunately, in the presence of transition metals, antioxidants, including polyphenols with potent antioxidant activities, may also exhibit pro-oxidant effects, which may irreversibly damage DNA. Therefore, antioxidants with strong free radical-scavenging abilities and devoid of pro-oxidant effects would be of immense biological importance. We report two antioxidant dendrimers with a surface rich in multiple phenolic hydroxyl groups, benzylic hydrogens, and electron-donating ring substituents that contribute to their potent free radical-quenching properties. To minimize their pro-oxidant effects, the dendrimers were designed with a metal-chelating tris(2-aminoethyl)amine (TREN) core. The dendritic antioxidants were prepared by attachment of six syringaldehyde or vanillin molecules to TREN by reductive amination. They exhibited potent radical-scavenging properties: 5 times stronger than quercetin and 15 times more potent than Trolox according to the 1,1-diphenyl-2-picrylhydrazyl assay. The antioxidant dendrimers also protected low-density lipoprotein, lysozyme, and DNA against 2,2'-azobis(2-amidinopropane) dihydrochloride-induced free radical damage. More importantly, unlike quercetin and Trolox, the two TREN antioxidant dendrimers did not damage DNA via their pro-oxidant effects when incubated with physiological amounts of copper ions. The dendrimers also showed no cytotoxicity toward Chinese hamster ovary cells.


Subject(s)
Antioxidants/pharmacology , Dendrimers , Reactive Oxygen Species/pharmacology , Animals , CHO Cells , Cricetinae , Cricetulus , DNA/drug effects , Electrophoresis, Agar Gel , Magnetic Resonance Spectroscopy , Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
8.
Bioorg Med Chem Lett ; 19(22): 6326-30, 2009 Nov 15.
Article in English | MEDLINE | ID: mdl-19822425

ABSTRACT

Three dendritic polyphenols (generation 1) were synthesized: a syringaldehyde-based dendrimer (1), a vanillin-based dendrimer (2), and an iodinated vanillin-based dendrimer (3). They all showed strong antioxidant activity according to the 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical assay. The syringaldehyde dendrimer was twice and 10 times stronger than quercetin and Trolox, respectively. The vanillin-based dendrimer and its more hydrophobic iodinated derivative were also more potent antioxidants than quercetin and Trolox. The DPPH order of potency was 1>2, 3>quercetin>Trolox. All three dendrimers also protected human LDL from free radical attack in a dose-dependent manner. Their order of free radical scavenging was 1>3>2>quercetin>Trolox. The increased hydrophobic nature of the iodinated derivative may have contributed to its better LDL protection than 2. Protection of linoleic acid oxidation was studied by the beta-carotene-linoleate assay. Dendrimer 1 was clearly superior to the other antioxidants in protecting the fatty acid. In case of DNA protection against free radical damage, the order of activity was 1>quercetin>2>3, Trolox. Pro-oxidant effect on copper-induced DNA oxidation showed the following order: quercetin, Trolox>1>2>3. Results of the study show that dendritic antioxidants, even at the generation 1 level, provide promising antioxidant properties for their potential use as drug candidates for diseases associated with oxidative stress.


Subject(s)
Flavonoids , Free Radical Scavengers , Phenols , Polyphenols , Quercetin , beta Carotene
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