Development of Synthetic Aminopeptidase N/CD13 Inhibitors to Overcome Cancer Metastasis and Angiogenesis

Cancer metastasis is a major barrier to its treatment and an important cause of patient death. Antimetastatic agents hold promise for patients with advanced metastatic tumors. Aminopeptidase N/CD13 (APN) is being pursued by many as an important target against cancer metastasis and angiogenesis, but there are few reports on the <i>in vivo</i> evaluation of synthetic APN inhibitors. Herein, a series of compounds targeting APN were synthesized and evaluated for their antimetastasis and antiangiogenesis potency both <i>in vitro</i> and <i>in vivo</i>. Excitingly, compounds <b>4m</b>, <b>4t</b>, and <b>4cc</b>, with the most potent APN inhibitory activities, displayed significant antimetastasis and antiangiogenesis effects <i>in vitro</i> and <i>in vivo</i>, suggesting that those synthetic APN inhibitors have the potential to overcome cancer metastasis and angiogenesis

DataSheet_1_Development and validation of a high-resolution T2WI-based radiomic signature for the diagnosis of lymph node status within the mesorectum in rectal cancer.docx

PurposeThe aim of this study was to explore the feasibility of a high-resolution T2-weighted imaging (HR-T2WI)-based radiomics prediction model for diagnosing metastatic lymph nodes (LNs) within the mesorectum in rectal cancer.MethodA total of 604 LNs (306 metastatic and 298 non-metastatic) from 166 patients were obtained. All patients underwent HR-T2WI examination and total mesorectal excision (TME) surgery. Four kinds of segmentation methods were used to select region of interest (ROI), including method 1 along the border of LNs; method 2 along the expanded border of LNs with an additional 2–3 mm; method 3 covering the border of LNs only; and method 4, a circle region only within LNs. A total of 1,409 features were extracted for each method. Variance threshold method, Select K Best, and Lasso algorithm were used to reduce the dimension. All LNs were divided into training and test sets. Fivefold cross-validation was used to build the logistic model, which was evaluated by the receiver operating characteristic (ROC) with four indicators, including area under the curve (AUC), accuracy (ACC), sensitivity (SE), and specificity (SP). Three radiologists with different working experience in diagnosing rectal diseases assessed LN metastasis respectively. The diagnostic efficiencies with each of four segmentation methods and three radiologists were compared to each other.ResultsFor the test set, the AUCs of four segmentation methods were 0.820, 0.799, 0.764, and 0.741; the ACCs were 0.725, 0.704, 0.709, and 0.670; the SEs were 0.756, 0.634, 0.700, and 0.589; and the SPs were 0.696, 0.772, 0.717, and 0.750, respectively. There was no statistically significant difference in AUC between the four methods (p > 0.05). Method 1 had the highest values of AUC, ACC, and SE. For three radiologists, the overall diagnostic efficiency was moderate. The corresponding AUCs were 0.604, 0.634, and 0.671; the ACCs were 0.601, 0.632, and 0.667; the SEs were 0.366, 0.552, and 0.392; and the SPs were 0.842, 0.715, and 0.950, respectively.ConclusionsThe proposed HR-T2WI-based radiomic signature exhibited a robust performance on predicting mesorectal LN status and could potentially be used for clinicians in order to determine the status of metastatic LNs in rectal cancer patients.</p

Discovery of Novel Pazopanib-Based HDAC and VEGFR Dual Inhibitors Targeting Cancer Epigenetics and Angiogenesis Simultaneously

Herein a novel series of pazopanib hybrids as polypharmacological antitumor agents were developed based on the crosstalk between histone deacetylases (HDACs) and vascular endothelial growth factor (VEGF) pathway. Among them, one <i>ortho</i>-aminoanilide <b>6d</b> and one hydroxamic acid <b>13f</b> exhibited considerable total HDACs and VEGFR-2 inhibitory activities. The HDAC inhibitory activities endowed <b>6d</b> and <b>13f</b> with potent antiproliferative activities, which was not observed in the approved VEGFR inhibitor pazopanib. Compounds <b>6d</b> and <b>13f</b> possessed comparable HDAC isoform selectivity profiles to the clinical class I HDAC inhibitor MS-275 and the approved pan-HDAC inhibitor SAHA, respectively. <b>6d</b> and <b>13f</b> also exhibited uncompromised multiple tyrosine kinases inhibitory activities relative to pazopanib. The intracellular dual inhibition to HDAC and VEGFR of <b>6d</b> and <b>13f</b> was validated by Western blot analysis. In both HUVECs tube formation assay and rat thoracic aorta rings assay, <b>6d</b> and <b>13f</b> showed comparable antiangiogenic potencies to pazopanib. What’s more, <b>6d</b> possessed desirable pharmacokinetic profiles with the oral bioavailability of 72% in SD rats and considerable in vivo antitumor efficacy in a human colorectal adenocarcinoma (HT-29) xenograft model

Design, Synthesis, and Antitumor Evaluation of Novel Histone Deacetylase Inhibitors Equipped with a Phenylsulfonylfuroxan Module as a Nitric Oxide Donor

On the basis of the strategy of creating multifunctional drugs, a novel series of phenylsulfonylfuroxan-based hydroxamates with histone deacetylase (HDAC) inhibitory and nitric oxide (NO) donating activities were designed, synthesized, and evaluated. The most potent NO donor–HDAC inhibitor (HDACI) hybrid, <b>5c</b>, exhibited a much greater in vitro antiproliferative activity against the human erythroleukemia (HEL) cell line than that of the approved drug SAHA (Vorinostat), and its antiproliferative activity was diminished by the NO scavenger hemoglobin in a dose-dependent manner. Further mechanism studies revealed that <b>5c</b> strongly induced cellular apoptosis and G1 phase arrest in HEL cells. Animal experiment identified <b>5c</b> as an orally active agent with potent antitumor activity in a HEL cell xenograft model. Interestingly, although compound <b>5c</b> was remarkably HDAC6-selective at the molecular level, it exhibited pan-HDAC inhibition in a western blot assay, which is likely due to class I HDACs inhibition caused by NO release at the cellular level