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1.
Cancers (Basel) ; 12(11)2020 Oct 23.
Article in English | MEDLINE | ID: mdl-33114147

ABSTRACT

Dysfunctions in epigenetic regulation play critical roles in tumor development and progression. Histone deacetylases (HDACs) and histone acetyl transferase (HAT) are functionally opposing epigenetic regulators, which control the expression status of tumor suppressor genes. Upregulation of HDAC activities, which results in silencing of tumor suppressor genes and uncontrolled proliferation, predominates in malignant tumors. Inhibition of the deacetylase activity of HDACs is a clinically validated cancer therapy strategy. However, current HDAC inhibitors (HDACi) have elicited limited therapeutic benefit against solid tumors. Here, we disclosed a class of HDACi that are selective for sub-class I HDACs and preferentially accumulate within the normal liver tissue and orthotopically implanted liver tumors. We observed that these compounds possess exquisite on-target effects evidenced by their induction of dose-dependent histone H4 hyperacetylation without perturbation of tubulin acetylation status and G0/G1 cell cycle arrest. Representative compounds 2 and 3a are relatively non-toxic to mice and robustly suppressed tumor growths in an orthotopic model of HCC as standalone agents. Collectively, our results suggest that these compounds may have therapeutic advantage against HCC relative to the current systemic HDACi. This prospect merits further comprehensive preclinical investigations.

2.
Angew Chem Int Ed Engl ; 59(35): 15161-15165, 2020 08 24.
Article in English | MEDLINE | ID: mdl-32415874

ABSTRACT

Herein, we report the development of an 18 F-labeled, activity-based small-molecule probe targeting the cancer-associated serine hydrolase NCEH1. We undertook a focused medicinal chemistry campaign to simultaneously preserve potent and specific NCEH1 labeling in live cells and animals, while permitting facile 18 F radionuclide incorporation required for PET imaging. The resulting molecule, [18 F]JW199, labels active NCEH1 in live cells at nanomolar concentrations and greater than 1000-fold selectivity relative to other serine hydrolases. [18 F]JW199 displays rapid, NCEH1-dependent accumulation in mouse tissues. Finally, we demonstrate that [18 F]JW199 labels aggressive cancer tumor cells in vivo, which uncovered localized NCEH1 activity at the leading edge of triple-negative breast cancer tumors, suggesting roles for NCEH1 in tumor aggressiveness and metastasis.


Subject(s)
Fluorine Radioisotopes/therapeutic use , Positron-Emission Tomography/methods , Sterol Esterase/metabolism , Animals , Female , Humans , Mice
3.
Bioorg Med Chem ; 28(6): 115345, 2020 03 15.
Article in English | MEDLINE | ID: mdl-32061484

ABSTRACT

Signal transducer and activator of transcription 3 (STAT3) is an oncogenic transcription factor which has been recognized as a promising cancer therapeutic target. Small molecule pyrimethamine (PYM) is a known direct inhibitor of activated STAT3 and it is currently under clinical trial. Also, histone deacetylase (HDAC) inhibition has been shown to indirectly attenuate STAT3 signaling through inhibition of STAT3 activation. Herein we described the design and biological profiling of two classes of PYM-conjugated HDAC inhibitors (HDACi). We observed that the class I PYM-HDACi compounds 12a-c potently inhibited HDACs 1 and 6 in cell free assays while a lead class II PYM-HDACi compound 23 showed a strong HDAC 6 selective inhibition. In a cell-based assay, 12a-c are preferentially cytotoxic to MDA-MB-231, a TNBC cell line that is highly STAT3-dependent, while 23 showed no such selective toxicity. Subsequent target validation studies revealed that a representative class I PYM-HDACi compound 12c elicited a signature of HDAC and STAT3 pathway inhibition intracellularly. Collectively, these data suggest that PYM-HDACi compounds are promising leads to develop targeted therapy for TNBC.


Subject(s)
Antineoplastic Agents/pharmacology , Drug Design , Histone Deacetylase Inhibitors/pharmacology , Pyrimethamine/pharmacology , Triple Negative Breast Neoplasms/drug therapy , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Proliferation/drug effects , Cells, Cultured , Chlorocebus aethiops , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Histone Deacetylase Inhibitors/chemical synthesis , Histone Deacetylase Inhibitors/chemistry , Humans , Molecular Structure , Pyrimethamine/chemical synthesis , Pyrimethamine/chemistry , STAT3 Transcription Factor/antagonists & inhibitors , STAT3 Transcription Factor/metabolism , Structure-Activity Relationship , Triple Negative Breast Neoplasms/metabolism
4.
Bioorg Med Chem ; 25(3): 1202-1218, 2017 02 01.
Article in English | MEDLINE | ID: mdl-28057407

ABSTRACT

We herein disclose a series of compounds with potent inhibitory activities towards histone deacetylases (HDAC) and cyclooxygenases (COX). These compounds potently inhibited the growth of cancer cell lines consistent with their anti-COX and anti-HDAC activities. While compound 2b showed comparable level of COX-2 selectivity as celecoxib, compound 11b outperformed indomethacin in terms of selectivity towards COX-2 relative to COX-1. An important observation with our lead compounds (2b, 8, 11b, and 17b) is their enhanced cytotoxicity towards androgen dependent prostate cancer cell line (LNCaP) relative to androgen independent prostate cancer cell line (DU-145). Interestingly, compounds 2b and 17b arrested the cell cycle progression of LNCaP in the S-phase, while compound 8 showed a G0/G1 arrest, similar to SAHA. Relative to SAHA, these compounds displayed tumor-selective cytotoxicity as they have low anti-proliferative activity towards healthy cells (VERO); an attribute that makes them attractive candidates for drug development.


Subject(s)
Antineoplastic Agents/pharmacology , Celecoxib/pharmacology , Cyclooxygenase Inhibitors/pharmacology , Histone Deacetylase Inhibitors/pharmacology , Histone Deacetylases/metabolism , Indomethacin/pharmacology , Prostaglandin-Endoperoxide Synthases/metabolism , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Celecoxib/chemical synthesis , Celecoxib/chemistry , Cell Cycle/drug effects , Cell Line , Cell Proliferation/drug effects , Cell Survival/drug effects , Cyclooxygenase Inhibitors/chemical synthesis , Cyclooxygenase Inhibitors/chemistry , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Histone Deacetylase Inhibitors/chemical synthesis , Histone Deacetylase Inhibitors/chemistry , Humans , Indomethacin/chemical synthesis , Indomethacin/chemistry , Models, Molecular , Molecular Structure , Structure-Activity Relationship
5.
Future Med Chem ; 8(17): 2091-2112, 2016 Nov.
Article in English | MEDLINE | ID: mdl-27774793

ABSTRACT

Liposomes are biodegradable and biocompatible self-forming spherical lipid bilayer vesicles. They can encapsulate and deliver one or more hydrophobic and hydrophilic therapeutic agents with poor therapeutic indices to tumor sites. Properties such as lipid bilayer fluidity, charge, size and surface hydration can be modified to extend liposome circulation time in the bloodstream and enhance efficacy. The focus of this review is on ligand-conjugated liposomes and their potential application in tumor-targeted delivery. Ligand-conjugated liposomes are designed to target receptors which are overexpressed on tumor cells to decrease drugs side effects by enhancing their selective delivery to tumor site. Despite the extensive research in this area, no small molecule ligand-conjugated liposome has been approved up to date for cancer therapy.

6.
Bioorg Med Chem ; 23(24): 7543-64, 2015 Dec 15.
Article in English | MEDLINE | ID: mdl-26585275

ABSTRACT

Inhibition of the enzymatic activity of histone deacetylase (HDAC) is a promising therapeutic strategy for cancer treatment and several distinct small molecule histone deacetylase inhibitors (HDACi) have been reported. We have previously identified a new class of non-peptide macrocyclic HDACi derived from 14- and 15-membered macrolide skeletons. In these HDACi, the macrocyclic ring is linked to the zinc chelating hydroxamate moiety through a para-substituted aryl-triazole cap group. To further delineate the depth of the SAR of this class of HDACi, we have synthesized series of analogous compounds and investigated the influence of various substitution patterns on their HDAC inhibitory, anti-proliferative and anti-inflammatory activities. We identified compounds 25b and 38f with robust anti-proliferative activities and compound 26f (IC50 47.2 nM) with superior anti-inflammatory (IC50 88 nM) activity relative to SAHA.


Subject(s)
Anti-Inflammatory Agents/chemistry , Antineoplastic Agents/chemistry , Cell Proliferation/drug effects , Histone Deacetylase Inhibitors/chemistry , Macrolides/chemistry , Animals , Anti-Inflammatory Agents/pharmacology , Antineoplastic Agents/pharmacology , Cell Line , Cell Line, Tumor , Chlorocebus aethiops , Histone Deacetylase Inhibitors/pharmacology , Humans , Macrolides/pharmacology , Neoplasms/drug therapy , Structure-Activity Relationship , Vero Cells
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