Design, Synthesis, and Antitumor Evaluation of 4‑Amino-(1<i>H</i>)‑pyrazole Derivatives as JAKs Inhibitors

Abnormalities in the JAK/STAT signaling pathway lead to many diseases such as immunodeficiency, inflammation, and cancer. Herein, we designed and synthesized a series of 4-amino-(1<i>H</i>)-pyrazole derivatives as potent JAKs inhibitors for cancer treatment. Results from <i>in vitro</i> protein kinase inhibition experiments indicated that compounds <b>3a</b>–<b>f</b> and <b>11b</b> are potent JAKs inhibitors. For example, the IC₅₀ values of compound <b>3f</b> against JAK1, JAK2, and JAK3 were 3.4, 2.2, and 3.5 nM, respectively. In cell culture experiments, compound <b>3f</b> showed potent antiproliferative activity against various cell lines (PC-3, HEL, K562, MCF-7, and MOLT4) at low micromolar levels, while compound <b>11b</b> showed selective cytotoxicity at submicromolar levels against HEL (IC₅₀: 0.35 μM) and K562 (IC₅₀: 0.37 μM) cell lines. It is worth noting that both <b>3f</b> and <b>11b</b> showed more potent antiproliferative activities than the approved JAKs inhibitor Ruxolitinib

sj-pdf-1-imr-10.1177_03000605231211771 - Supplemental material for FKBP5 associated CD8 T cell infiltration is a novel prognostic biomarker in luminal B breast cancer

Supplemental material, sj-pdf-1-imr-10.1177_03000605231211771 for FKBP5 associated CD8 T cell infiltration is a novel prognostic biomarker in luminal B breast cancer by Fei Tong, Genlin Lu, Jie Zang, Dingji Hao, Wangjue Xu, Jida Chen, Qiong Ding and Hanchu Xiong in Journal of International Medical Research</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

Identification of HBV-MLL4 Integration and Its Molecular Basis in Chinese Hepatocellular Carcinoma

<div><p>To gain molecular insights of HBV integration that may contribute to HCC tumorigenesis, we performed whole transcriptome sequencing and whole genome copy number profiling of hepatocellular carcinoma (HCC) samples from 50 Chinese patients. We identified a total of 33 HBV-human integration sites in 16 of 44 HBV-positive HCC tissues, which were enriched in HBV genotype C-infected patients. In addition, significantly recurrent HBV-MLL4 integration (18%; 8/44) was found in this cohort of patients. Using long-range PCR and Sanger sequencing, we comprehensively characterized gDNA and cDNA sequences that encode for the HBV-MLL4 transcripts, and we revealed that HBV integration into <i>MLL4</i> exons led to much higher mRNA expression of <i>MLL4</i> than the integration into <i>MLL4</i> introns due to an alternative splicing mechanism. Moreover, the HBV-MLL4 integration occurred almost exclusively in <i>CTNNB1</i> and <i>TP53</i> wild-type patients. The integration was also associated with a distinct gene expression profile. In conclusion, this is the first report on the molecular basis of the <i>MLL4</i> integration driving <i>MLL4</i> over-expression. HBV-MLL4 integration occurred frequently in Chinese HCC patients, representing a unique molecular segment for HCC with HBV infection.</p></div

Gene expression profile of HCC harboring MLL4 integration.

<p>Unsupervised hierarchical clustering of mRNA expression across all 50 HCC samples with 4 adjacent normal samples. (A) Heatmap overview of the gene expression pattern. (B) A list of 31 genes that were distinctly over-expressed in the 8 <i>MLL4</i> integration positive HCC samples. (C) An additional 17 genes that were distinctly over-expressed in 3 higher-expressed <i>MLL4</i> HCC samples carrying <i>MLL4</i> exon integration.</p

cDNA structure of HBV integration.

<p>Cartoon illustrating HBV-integrated cDNA structures. Full-length (315T, 316T, and 328T) and partially inserted cDNA sequences are shown for each sample, noted with alternative splicing isoforms for each transcript.</p

Additional file 1 of Pathologically catalyzed physical coating restores the intestinal barrier for inflammatory bowel disease therapy

Supplementary Material

Genome landscape of HCC and related HBV.

<p>RNASeq and aCGH data in HCC tissues were analyzed. (A) Model of the HBV genotype C genome, including the well-known HBV genome within the circle, and HBV mRNA expression [blue area] and integration sites [red triangle]. (B) HCC genomic landscape by HBV integration. The gene copy number gain is shown in blue, the copy number loss in red, and the human genome sites involved in virus integration at each chromosome as a red triangle.</p

Genomic structures of HBV integration.

<p>HBV insertions are shown as circles marked with insertion positions. <i>MLL4</i> insertion sites are marked as purple (upstream) and blue arrows (downstream), noted with the exact integration position on human gene <i>MLL4</i>.</p

Clinical Characteristics of HCC Samples.

<p>Note:</p><p>^# Some patients’ clinic information is not complete, like HBV infection type, tumor size, tumor number, AFP level.</p><p>*P-value is significant. All P-values were calculated by fisher exact test between genotype C and B group.</p><p>Clinical Characteristics of HCC Samples.</p