Jian Ding

Publications of Jian Ding

• Anatomy of the giant component: The strictly supercritical regime

  Authors: Jian Ding, Eyal Lubetzky, Yuval Peres

  02/2012;

  In a recent work of the authors and Kim, we derived a complete description of the largest component of the Erd\H{o}s-R\'enyi random graph $G(n,p)$ as it emerges from the critical window, i.e. for $pIn a recent work of the authors and Kim, we derived a complete description of the largest component of the Erd\H{o}s-R\'enyi random graph $G(n,p)$ as it emerges from the critical window, i.e. for $p = (1+\epsilon)/n$ where $\epsilon^3 n \to\infty$ and $\epsilon=o(1)$, in terms of a tractable contiguous model. Here we provide the analogous description for the supercritical giant component, i.e., the largest component of $G(n,p)$ for $p = \lambda/n$ where $\lambda>1$ is fixed. The contiguous model is roughly as follows: Take a random degree sequence and sample a random multigraph with these degrees to arrive at the kernel; Replace the edges by paths whose lengths are i.i.d. geometric variables to arrive at the 2-core; Attach i.i.d. Poisson Galton-Watson trees to the vertices for the final giant component. As in the case of the emerging giant, we obtain this result via a sequence of contiguity arguments at the heart of which are Kim's Poisson-cloning method and the Pittel-Wormald local limit theorems.

• The anti-cancer activity of dihydroartemisinin is associated with induction of iron-dependent endoplasmic reticulum stress in colorectal carcinoma HCT116 cells.

  Authors: Jin-Jian Lu, Si-Meng Chen, Xiao-Wei Zhang, Jian Ding, Ling-Hua Meng

  Investigational new drugs. 12/2011; 29(6):1276-83.

  Dihydroartemisinin (DHA), the main active metabolite of artemisinin derivatives, is among the artemisinin derivatives possessing potent anti-malarial and anti-cancer activities. In the present study,Dihydroartemisinin (DHA), the main active metabolite of artemisinin derivatives, is among the artemisinin derivatives possessing potent anti-malarial and anti-cancer activities. In the present study, we found that DHA displayed significant anti-proliferative activity in human colorectal carcinoma HCT116 cells, which may be attributed to its induction of G1 phase arrest and apoptosis. To further elucidate the mechanism of action of DHA, a proteomic study employed two-dimensional gel electrophoresis (2-DE) and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) was performed. Glucose-regulated protein 78 (GRP78), which is related with endoplasmic reticulum stress (ER stress), was identified to be significantly up-regulated after DHA treatment. Further study demonstrated that DHA enhanced expression of GRP78 as well as growth arrest and DNA-damage-inducible gene 153 (GADD153, another ER stress-associated molecule) at both mRNA and protein levels. DHA treatment also led to accumulation of GADD153 in cell nucleus. Moreover, pretreatment of HCT116 cells with the iron chelator deferoxamine mesylate salt (DFO) abrogated induction of GRP78 and GADD153 upon DHA treatment, indicating iron is required for DHA-induced ER stress. This result is consistent with the fact that the anti-proliferative activity of DHA is also mediated by iron. We thus suggest the unbalance of redox may result in DHA-induced ER stress, which may contribute, at least in part, to its anti-cancer activity.

• Design, synthesis and biological evaluation of substituted 11H-benzo[a]carbazole-5-carboxamides as novel antitumor agents.

  Authors: Yu-Qin Wang, Xiao-Hua Li, Qian He, Yi Chen, Yu-Yuan Xie, Jian Ding, Ze-Hong Miao, Chun-Hao Yang

  European journal of medicinal chemistry. 12/2011; 46(12):5878-84.

  A series of novel 11H-benzo[a]carbazole-5-carboxamide derivatives were designed, synthesized and evaluated for their antitumor activity against human cancer A549 and HCT-116 cell lines. Most of theA series of novel 11H-benzo[a]carbazole-5-carboxamide derivatives were designed, synthesized and evaluated for their antitumor activity against human cancer A549 and HCT-116 cell lines. Most of the compounds showed potent antitumor activities, and compound 8 displayed remarkable in vitro and in vivo anticancer activity comparable to that of amonafide.

• Constituents of Trigonostemon heterophyllus.

  Authors: Shi-Hui Dong, Hong-Bing Liu, Cheng-Hui Xu, Jian Ding, Jian-Min Yue

  Journal of natural products. 11/2011; 74(12):2576-81.

  Six new diterpenoids, 1-6, a new prenylated sesquiterpenoid, 7, and six known compounds were isolated from Trigonostemon heterophyllus. The structures of 1-7 were elucidated on the basis of NMR andSix new diterpenoids, 1-6, a new prenylated sesquiterpenoid, 7, and six known compounds were isolated from Trigonostemon heterophyllus. The structures of 1-7 were elucidated on the basis of NMR and MS analysis. The daphnane diterpenoids trigoheterins A (1) and B (2) possess a rare 4,6-oxetane moiety within this compound class, and trigoheteric acid methyl ester (6) is the first example of a 15,16-dinor-3,4-seco-cleistanthane. Trigoheterin E (5) exhibited cytotoxic activity against the HL-60 (IC₅₀) 1.8 μM) and A-549 (IC₅₀ 10.0 μM) human cancer cell lines.

• The role of polymeric immunoglobulin receptor in inflammation-induced tumor metastasis of human hepatocellular carcinoma.

  Authors: Jing Ai, Qingjuan Tang, Yanlin Wu, Yang Xu, Teng Feng, Ruiyu Zhou, Yi Chen, Xin Gao, Qingfeng Zhu, Xihua Yue, Qiuming Pan, Siyun Xu, Jing Li, Min Huang, Jennifer Daugherty-Holtrop, Yuanzheng He, H Eric Xu, Jia Fan, Jian Ding, Meiyu Geng

  Journal of the National Cancer Institute. 11/2011; 103(22):1696-712.

  Expression of the polymeric immunoglobulin receptor (pIgR), a transporter of polymeric IgA and IgM, is commonly increased in response to viral or bacterial infections, linking innate and adaptiveExpression of the polymeric immunoglobulin receptor (pIgR), a transporter of polymeric IgA and IgM, is commonly increased in response to viral or bacterial infections, linking innate and adaptive immunity. Abnormal expression of pIgR in cancer was also observed, but its clinical relevance remains uncertain. A human hepatocellular carcinoma (HCC) tissue microarray (n = 254) was used to investigate the association between pIgR expression and early recurrence. An experimental lung metastasis model using severe combined immune-deficient mice was applied to determine the metastatic potential of Madin-Darby canine kidney (n = 5 mice per group) and SMMC-7721 (n = 12 mice per group) cells overexpressing pIgR vs control cells. RNA interference, immunoprecipitation, and immunoblotting were performed to investigate the potential role for pIgR in the induction of epithelial-mesenchymal transition (EMT). In vitro studies (co-immunoprecipitation, immunoblotting, and migration, invasion, and adhesion assays) were used to determine the mechanisms behind pIgR-mediated metastasis. All statistical tests were two-sided. High expression of pIgR was statistically significantly associated with early recurrence in early-stage HCC and in hepatitis B surface antigen-positive HCC patients (log-rank P = .02). Mice injected with pIgR-overexpressing cells had a statistically significantly higher number of lung metastases compared with respective control cells (Madin-Darby canine kidney cells: pIgR mean = 29.4 metastatic nodules per lung vs control mean = 0.0 metastatic nodules per lung, difference = 29.4 metastatic nodules per lung, 95% confidence interval = 13.0 to 45.8, P = .001; SMMC-7721 cells: pIgR mean = 10.4 metastatic nodules per lung vs control mean = 2.2 metastatic nodules per lung, difference = 8.2 metastatic nodules per lung, 95% confidence interval = 1.0 to 15.5, P = .03). Furthermore, high expression of pIgR was sufficient to induce EMT through activation of Smad signaling. pIgR plays a role in the induction of EMT. Our results identify pIgR as a potential link between hepatitis B virus-derived hepatitis and HCC metastasis and provide evidence in support of pIgR as a prognostic biomarker for HCC and a potential therapeutic target.

• Discovery and bioactivity of 4-(2-arylpyrido[3',2':3,4]pyrrolo[1,2-f][1,2,4]triazin-4-yl) morpholine derivatives as novel PI3K inhibitors.

  Authors: Jia Wang, Xiang Wang, Yanhong Chen, Simeng Chen, Guang Chen, Linjiang Tong, Linghua Meng, Yuyuan Xie, Jian Ding, Chunhao Yang

  Bioorganic & medicinal chemistry letters. 11/2011; 22(1):339-42.

  PI3K is a promising therapeutic target for cancer. With PI-103 as the lead compound, we designed and synthesized 4-(2-arylpyrido[3',2':3,4]pyrrolo[1,2-f][1,2,4]triazin-4-yl)morpholine derivatives. 9,PI3K is a promising therapeutic target for cancer. With PI-103 as the lead compound, we designed and synthesized 4-(2-arylpyrido[3',2':3,4]pyrrolo[1,2-f][1,2,4]triazin-4-yl)morpholine derivatives. 9, 10a, 10d, 10e had the IC(50) against PI3Kα comparable with PI-103. All of the compounds showed selectivity over 15 tested protein kinases and anti-proliferative activity at micromolar concentration against several cancer cell lines.

• Characterization of dihydroartemisinin-resistant colon carcinoma HCT116/R cell line.

  Authors: Jin-Jian Lu, Si-Meng Chen, Jian Ding, Ling-Hua Meng

  Molecular and cellular biochemistry. 09/2011; 360(1-2):329-37.

  Dihydroartemisinin (DHA) is an important artemisinin derivative and presents profound anti-tumor potential. A DHA-resistant cell line named HCT116/R derived from colon carcinoma cell line HCT116 wasDihydroartemisinin (DHA) is an important artemisinin derivative and presents profound anti-tumor potential. A DHA-resistant cell line named HCT116/R derived from colon carcinoma cell line HCT116 was established in our previous study. Herein, we found that HCT116/R cells were much more resistant to DHA- or artesunate-induced proliferation inhibition and more tolerant to DHA-induced cell cycle arrest and apoptosis compared with those of the parent HCT116 cells. The protein levels of P-glycoprotein and MDR-associated protein 1 and the accumulation of doxorubicin in cells were similar in both cell lines. Moreover, HCT116/R cells were still sensitive to camptothecin- and doxorubicin-induced cell growth inhibition. To further explore the characterization of HCT116/R cell line, a proteomic study employing two-dimensional gel electrophoresis and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry was performed. Eight different expressed proteins between the two cell lines were identified including some heat shock proteins, annexins, etc. This study not only indicates that exposure to DHA may not induce a tumor multi-drug-resistant phenotype but also affords new clues for the further investigation of the anti-cancer mechanisms of DHA and other artemisinin derivatives.

• The short-time treatment with curcumin sufficiently decreases cell viability, induces apoptosis and copper enhances these effects in multidrug-resistant K562/A02 cells.

  Authors: Jin-Jian Lu, Yu-Jun Cai, Jian Ding

  Molecular and cellular biochemistry. 09/2011; 360(1-2):253-60.

  The anti-cancer activities of curcumin (CUR), a polyphenol derived from the plant Curcuma longa, has been extensively studied. In the present study, we found that CUR displayedThe anti-cancer activities of curcumin (CUR), a polyphenol derived from the plant Curcuma longa, has been extensively studied. In the present study, we found that CUR displayed anti-multidrug-resistant (MDR) activity in K562/A02 cells. A short-time treatment with CUR sufficiently and equally induced DNA damage, decreased cell viability, and triggered apoptosis in parent K562 and MDR K562/A02 cells. The short-time treatment with CUR also caused decrease of pro-caspase 3 in both cell lines and decrease of pro-caspase 9, increase of PARP cleavage and the ratio of Bax/Bcl-xL in MDR K562/A02 cells. Further experiment revealed that CUR was capable of down-regulating P-glycoprotein in MDR K562/A02 cells. Moreover, we observed that Cu(2+) enhanced CUR-mediated apoptosis which was blocked by antioxidants N-acetyl-cysteine and catalase. In summary, the short-time treatment with CUR sufficiently induced DNA damage, decreased cell viability and triggered apoptosis in MDR K562/A02 cells and Cu(2+) enhanced CUR-mediated apoptosis which due to reactive oxygen species generation.

• MT119, a new planar-structured compound, targets the colchicine site of tubulin arresting mitosis and inhibiting tumor cell proliferation.

  Authors: Zhixiang Zhang, Tao Meng, Na Yang, Wei Wang, Bing Xiong, Yi Chen, Lanping Ma, Jingkang Shen, Ze-Hong Miao, Jian Ding

  International journal of cancer. Journal international du cancer. 07/2011; 129(1):214-24.

  Microtubule-targeted drugs are now indispensable for the therapy of various cancer types worldwide. In this article, we report MT119 [6-[2-(4-methoxyphenyl)Microtubule-targeted drugs are now indispensable for the therapy of various cancer types worldwide. In this article, we report MT119 [6-[2-(4-methoxyphenyl) -ethyl]-9-[(pyridine-3-ylmethyl)amino]pyrido[2',1':2,3]imida-zo[4,5-c]isoquinolin-5(6H)-one] as a new microtubule-targeted agent. MT119 inhibited tubulin polymerization significantly both in tumor cells and in cell-free systems, which was followed by the disruption of mitotic spindle assembly. Surface plasmon resonance-based analyses showed that MT119 bound to purified tubulin directly, with the K(D) value of 10.6 μM. The binding of MT119 in turn caused tubulin conformational changes as evidenced by the quenched tryptophan fluorescence, the reduction of the bis-ANS reactivity and the decreased DTNB-sulfhydryl reaction rate. Competitive binding assays further revealed that MT119 bound to tubulin at its colchicine site. Consequently, by inhibiting tubulin polymerization, MT119 arrested different tumor cells at mitotic phase, which contributed to its potent antitumor activity in vitro. MT119 was also similarly cytotoxic to vincristine-, adriamycin- or mitoxantrone-resistant cancer cells and to their corresponding parental cells. Together, these data indicate that MT119 represents a new class of colchicine-site-targeted inhibitors against tubulin polymerization, which might be a promising starting point for future cancer therapeutics.

• Drug transporter-independent liver cancer cell killing by a marine steroid methyl spongoate via apoptosis induction.

  Authors: Yi Jiang, Ze-Hong Miao, Lei Xu, Bing Yu, Jing-Xu Gong, Lin-Jiang Tong, Yi Chen, Zhao-Li Zhou, Hong-Chun Liu, Yi Wang, Yue-Wei Guo, Jian Ding

  The Journal of biological chemistry. 06/2011; 286(30):26461-9.

  Hepatocellular carcinoma (HCC) is inherently resistant to the majority of clinical anticancer drugs. To obtain drugs that can circumvent or evade such inherent drug resistance of HCC, we investigatedHepatocellular carcinoma (HCC) is inherently resistant to the majority of clinical anticancer drugs. To obtain drugs that can circumvent or evade such inherent drug resistance of HCC, we investigated the effect of the marinely derived steroid methyl spongoate (MESP) on HCC cells. MESP displayed potent cell killing against a panel of six HCC cell lines, independent of their expression of drug transporters. MESP did not change the function of the drug transporters, and its cell killing was not impaired in multidrug-resistant cancer cells overexpressing the transporters. The cell killing of MESP was irrelevant to estrogen or androgen signaling and was not associated with cell cycle progression, inhibition of microtubules, and topoisomerases. In contrast, MESP potently induced apoptosis via activation of a proapoptotic caspase cascade and relief of the suppression of antiapoptotic signal transducers and activators of transcription 3 (STAT3) signaling. MESP inhibited the phosphorylation of STAT3, a critical survival signaling factor that reduced the expression of the antiapoptotic protein x-linked inhibitor of apoptosis protein but enhanced the expression of the proapoptotic protein Bax, thus promoting caspase-dependent apoptosis. These data reveal that MESP may well serve as an important candidate drug lead for HCC therapy.

• Acenaphtho[1,2-b]pyrrole-based selective fibroblast growth factor receptors 1 (FGFR1) inhibitors: design, synthesis, and biological activity.

  Authors: Zhuo Chen, Xin Wang, Weiping Zhu, Xianwen Cao, Linjiang Tong, Honglin Li, Hua Xie, Yufang Xu, Shaoying Tan, Dong Kuang, Jian Ding, Xuhong Qian

  Journal of medicinal chemistry. 06/2011; 54(11):3732-45.

  A novel series of acenaphtho[1,2-b]pyrrole derivatives as potent and selective inhibitors of fibroblast growth factor receptor 1 (FGFR1) were designed and synthesized. In silico target predictionA novel series of acenaphtho[1,2-b]pyrrole derivatives as potent and selective inhibitors of fibroblast growth factor receptor 1 (FGFR1) were designed and synthesized. In silico target prediction revealed that tyrosine kinases might be the potential targets of the representative compound 2, which was subsequently validated by enzyme-linked immunosorbent assay (ELISA) for its selective and active FGFR1 inhibition of various tyrosine kinases. The structure-activity relationship (SAR) analysis aided by molecular docking simulation in the ATP-binding site demonstrated that acenaphtho[1,2-b]pyrrole carboxylic acid esters (2-5) are potent inhibitors of FGFR1 with IC(50) values ranging from 19 to 77 nM. Furthermore, these compounds exhibited favorable growth inhibition property against FGFR-expressing cancer cell lines with IC(50) values ranging from micromolar to submicromolar. Western blotting analysis showed that compounds 2, 3, and 2b inhibited activation of FGFR1 and extracellular-signal regulated kinase 1/2 (Erk1/2).

• Establishment of platform for screening insulin-like growth factor-1 receptor inhibitors and evaluation of novel inhibitors.

  Authors: Lin-jiang Tong, Hua Xie, Ting Peng, Xiao-feng Liu, Xian-liang Xin, Xun Huang, Si-meng Chen, Hong-yan Liu, Hong-lin Li, Mei-yu Geng, Ming Yin, Jian Ding

  Acta pharmacologica Sinica. 06/2011; 32(7):930-8.

  The insulin-like growth factor-1 receptor (IGF1R) is over-expressed in a wide variety of tumors and contributes to tumor cell proliferation, metastasis and drug resistance. The aim of this study wasThe insulin-like growth factor-1 receptor (IGF1R) is over-expressed in a wide variety of tumors and contributes to tumor cell proliferation, metastasis and drug resistance. The aim of this study was to establish a sensitive screening platform to identify novel IGF1R inhibitors. The catalytic domain of IGF1R was expressed using the Bac-to-Bac baculovirus expression system. The screening platform for IGF1R inhibitors was established based on ELISA. The binding profile of IGF1R with the inhibitors was predicted with molecular docking and then subjected to the surface plasmon resonance (SPR) approach. The growth inhibition of cancer cells by the inhibitors was assessed with MTT assay. Apoptosis was analyzed using flow cytometry and Western blotting. A naturally occurring small molecule compound hematoxylin was identified as the most potent inhibitor (IC₅₀ value=1.8±0.1 μmol/L) within a library of more than 200 compounds tested. Molecular simulation predicted the possible binding mode of hematoxylin with IGF1R. An SPR assay further confirmed that hematoxylin bound directly to IGF1R with high binding affinity (Kd=4.2 × 10⁻⁶ mol/L). In HL-60 cancer cells, hematoxylin inactivated the phosphorylation of IGF1R and downstream signaling and therefore suppressed cell proliferation. Mechanistic studies revealed that hematoxylin induced apoptosis in HL-60 cells via both extrinsic and intrinsic pathways. A simple, sensitive ELISA-based screening platform for identifying IGF1R inhibitors was established. Hematoxylin was identified as a promising IGF1R inhibitor with effective antitumor activity that deserves further investigation.

• Daphnane-type diterpenoids from Trigonostemon howii.

  Authors: Shi-Hui Dong, Chuan-Rui Zhang, Cheng-Hui Xu, Jian Ding, Jian-Min Yue

  Journal of natural products. 05/2011; 74(5):1255-61.

  Nine new daphnane-type diterpenoids (1-9), named trigohownins A-I, and four known analogues were isolated from Trigonostemon howii. Their structures were elucidated on the basis of extensive NMR andNine new daphnane-type diterpenoids (1-9), named trigohownins A-I, and four known analogues were isolated from Trigonostemon howii. Their structures were elucidated on the basis of extensive NMR and MS analyses. Trigohownins A (1) and D (4) exhibited moderate cytotoxic activity against the HL-60 tumor cell line, with IC50 values of 17.0 and 9.3 μM, respectively.

• Curcumin induces DNA damage and caffeine-insensitive cell cycle arrest in colorectal carcinoma HCT116 cells.

  Authors: Jin-Jian Lu, Yu-Jun Cai, Jian Ding

  Molecular and cellular biochemistry. 04/2011; 354(1-2):247-52.

  Curcumin (CUR), a polyphenol derived from the plant Curcuma longa, displays potential anti-cancer activity. One of the mechanisms stems from its ability to elicit cell cycle arrest followed byCurcumin (CUR), a polyphenol derived from the plant Curcuma longa, displays potential anti-cancer activity. One of the mechanisms stems from its ability to elicit cell cycle arrest followed by suppression of cell proliferation. Herein, we reported that CUR significantly induced DNA damage and mediated S and G2/M phase arrest in colorectal carcinoma HCT116 cells. Unlike etoposide, a classical topoisomerase II inhibitor, CUR-triggered G2/M phase arrest was hardly reversed by caffeine (CAFF) which is an inhibitor of activated ataxia-telangiectasia-mutated (ATM)/ATM- and Rad3-related (ATR), indicating that ATM and ATR signaling pathways may be not involved in CUR-mediated S and G2/M phase arrest in HCT116 cells. Furthermore, we demonstrated that CUR caused mitosis arrest in HCT116 cells by using mitotic protein monoclonal antibody-2 as a mitosis marker and the surface plasmon resonance assay. The findings provide new mechanisms of cell proliferation inhibition triggered by CUR in HCT116 cells.

• The role of histone deacetylase 7 (HDAC7) in cancer cell proliferation: regulation on c-Myc.

  Authors: Caihua Zhu, Qin Chen, Zuoquan Xie, Jing Ai, Linjiang Tong, Jian Ding, Meiyu Geng

  Journal of molecular medicine (Berlin, Germany). 03/2011; 89(3):279-89.

  Histone deacetylases (HDACs) play fundamental roles in the epigenetic regulation of gene expression and contribute to the growth, differentiation, and apoptosis of cancer cells. Although HDACs areHistone deacetylases (HDACs) play fundamental roles in the epigenetic regulation of gene expression and contribute to the growth, differentiation, and apoptosis of cancer cells. Although HDACs are recognized to be closely related to cancer development and altered expression of certain HDACs is observed in tumor samples, the arcane characters of HDACs in tumorigenesis have not been fully illustrated. Herein, we report that HDAC7 is a crucial player in cancer cell proliferation. Knockdown of HDAC7 resulted in significant G(1)/S arrest in different cancer cell lines. Subsequent investigations indicated that HDAC7 silencing blocked cell cycle progression through suppressing c-Myc expression and increasing p21 and p27 protein levels. The ectopic expression of c-Myc in turn antagonized the cell cycle arrest and repressed the elevation of p21 and p27 in HDAC7 silencing setting. Of note, HDAC7 deficiency was further identified to induce cellular senescence program, which was also reversed by c-Myc re-expression. Further chromatin immunoprecipitation assays indicated that HDAC7 directly binds with c-Myc gene and HDAC7 silencing decreased c-Myc mRNA level via reducing histone H3/H4 acetylation and repressing the association of RNA polymerase II (RNAP II) with c-Myc gene. Taken together, our findings highlight for the first time an unrecognized link between HDAC7 and c-Myc and offer a novel mechanistic insight into the contribution of HDAC7 to tumor progression.

• Oligomannurarate sulfate sensitizes cancer cells to doxorubicin by inhibiting atypical activation of NF-κB via targeting of Mre11.

  Authors: Jing Zhang, Xianliang Xin, Qin Chen, Zuoquan Xie, Min Gui, Yi Chen, Liping Lin, Jianming Feng, Qiuning Li, Jian Ding, Meiyu Geng

  International journal of cancer. Journal international du cancer. 03/2011; 130(2):467-77.

  Aberrant regulation of nuclear factor kappa B (NF-κB) transcription factor is involved in cancer development, progression and resistance to chemotherapy. JG3, a marine-derived oligomannurarateAberrant regulation of nuclear factor kappa B (NF-κB) transcription factor is involved in cancer development, progression and resistance to chemotherapy. JG3, a marine-derived oligomannurarate sulfate, was reported as a heparanase and NF-κB inhibitor to significantly block tumor growth and metastasis in various animal models. However, the detailed functional mechanism remains unclear. Here, we report that JG3 inhibits NF-κB activation by specifically antagonizing the doxorubicin-triggered Ataxia-telangiectasia-mutated kinase (ATM) and the sequential MEK/ERK/p90Rsk/IKK signaling pathway but does not interfere with TNF-α-mediated NF-κB activation. This selective inactivation of the specific NF-κB cascade is attributed to the binding capacity of JG3 for Mre11, a major sensor of DNA double-strand breaks (DSB). Based on this selective mechanism, JG3 showed synergistic effect with doxorubicin in a panel of tumor cells and did not affect immune system function as shown in the in vivo delayed-type hypersensitivity (DTH) and hemolysis assays. All these highlight the clinical potential of JG3 as a favorable sensitizer in cancer therapy. In addition, identification of Mre11 as a potential target in the development of NF-κB inhibitors provides a platform for the further development of effective anticancer agents.

• Palmarumycins BG1-BG7 and preussomerin BG1: establishment of their absolute configurations using theoretical calculations of electronic circular dichroism spectra.

  Authors: You-Sheng Cai, Tibor Kurtán, Ze-Hong Miao, Attila Mándi, István Komáromi, Hai-Li Liu, Jian Ding, Yue-Wei Guo

  The Journal of organic chemistry. 02/2011; 76(6):1821-30.

  Palmarumycins BG1-BG7 (1-7), seven new compounds related to palmarumycins, were isolated from the aerial parts of Bruguiera gymnorrhiza as well as a new preussomerin derivative BG1 (8). ThePalmarumycins BG1-BG7 (1-7), seven new compounds related to palmarumycins, were isolated from the aerial parts of Bruguiera gymnorrhiza as well as a new preussomerin derivative BG1 (8). The structures of these compounds were determined mainly by the analysis of their NMR and MS data, and their relative configurations were assigned on the basis of their (3)J(H,H) coupling constants. Compounds 4 and 7 have a sulfate group that is unprecedented among members of spirodioxynaphthalene-type natural products. The absolute configurations of 1-8 were determined by TDDFT CD calculations of the solution conformers. Compound 5 displayed inhibitory activity against HL 60 and MCF-7 cell lines.

• AST1306, a novel irreversible inhibitor of the epidermal growth factor receptor 1 and 2, exhibits antitumor activity both in vitro and in vivo.

  Authors: Hua Xie, Liping Lin, Linjiang Tong, Yong Jiang, Mingyue Zheng, Zhuo Chen, Xiaoyan Jiang, Xiaowei Zhang, Xiaowei Ren, Wenchao Qu, Yang Yang, Hua Wan, Yi Chen, Jianping Zuo, Hualiang Jiang, Meiyu Geng, Jian Ding

  PloS one. 01/2011; 6(7):e21487.

  Despite the initial response to the reversible, ATP-competitive quinazoline inhibitors that target ErbB-family, such a subset of cancer patients almost invariably develop resistance. Recent studiesDespite the initial response to the reversible, ATP-competitive quinazoline inhibitors that target ErbB-family, such a subset of cancer patients almost invariably develop resistance. Recent studies have provided compelling evidence that irreversible ErbB inhibitors have the potential to override this resistance. Here, we found that AST1306, a novel anilino-quinazoline compound, inhibited the enzymatic activities of wild-type epidermal growth factor receptor (EGFR) and ErbB2 as well as EGFR resistant mutant in both cell-free and cell-based systems. Importantly, AST1306 functions as an irreversible inhibitor, most likely through covalent interaction with Cys797 and Cys805 in the catalytic domains of EGFR and ErbB2, respectively. Further studies showed that AST1306 inactivated pathways downstream of these receptors and thereby inhibited the proliferation of a panel of cancer cell lines. Although the activities of EGFR and ErbB2 were similarly sensitive to AST1306, ErbB2-overexpressing cell lines consistently exhibited more sensitivity to AST1306 antiproliferative effects. Consistent with this, knockdown of ErbB2, but not EGFR, decreased the sensitivity of SK-OV-3 cells to AST1306. In vivo, AST1306 potently suppressed tumor growth in ErbB2-overexpressing adenocarcinoma xenograft and FVB-2/N(neu) transgenic breast cancer mouse models, but weakly inhibited the growth of EGFR-overexpressing tumor xenografts. Tumor growth inhibition induced by a single dose of AST1306 in the SK-OV-3 xenograft model was accompanied by a rapid (within 2 h) and sustained (≥24 h) inhibition of both EGFR and ErbB2, consistent with an irreversible inhibition mechanism. Taken together, these results establish AST1306 as a selective, irreversible ErbB2 and EGFR inhibitor whose growth-inhibitory effects are more potent in ErbB2-overexpressing cells.

• PH006, a novel and selective Src kinase inhibitor, suppresses human breast cancer growth and metastasis in vitro and in vivo.

  Authors: Jin-gui Ma, He Huang, Si-meng Chen, Yi Chen, Xian-liang Xin, Li-ping Lin, Jian Ding, Hong Liu, Ling-hua Meng

  Breast cancer research and treatment. 12/2010; 130(1):85-96.

  The central role of Src in tumor progression and metastasis has validated it as an attractive therapeutic target for the treatment of human breast cancer. The aim of this study was to identifyThe central role of Src in tumor progression and metastasis has validated it as an attractive therapeutic target for the treatment of human breast cancer. The aim of this study was to identify potential Src kinase inhibitor, explore its activity, and mechanism of action in human breast cancer. A strategy integrating focused combinatorial library design, virtual screening, chemical synthesis, and high-throughput screening was adopted and a novel 6-hydrazinopurine-based inhibitor of c-Src kinase PH006 was obtained. The kinase enzymatic activities were measured by enzyme-linked immunosorbent assay. The binding mode between PH006 and Src was profiled by surface plasmon resonance approach and molecular simulation. The anti-proliferative activity was evaluated by Sulforhodamin B (SRB) and Colony formation. The anti-invasion and anti-migration activities were assessed by trans-well and wound healing assay. Results indicated that PH006 was an ATP-competitive Src inhibitor, which selectively inhibited c-Src with an IC₅₀ of 0.38 μM among a panel of 14 diverse tyrosine kinases. PH006 potently inhibited c-Src phosphorylation and c-Src-dependent signal transduction, resulting in inhibition of cell proliferation, migration, and invasion in human breast cancer MDA-MB-231 cells. Further study demonstrated that the anti-proliferative activity of PH006 was ascribed to its capability to arrest cells in G1 phase, while its anti-motility activity was related to suppression of MMP2/9 and HGF secretion. Moreover, PH006 exhibited potent activity against tumor growth as well as metastasis of human breast cancer MDA-MB-435 xenograft beard in nude mice, which was accompanied with reduced Src/FAK signaling in tumor tissue. Taken together, PH006 is a novel selective inhibitor of c-Src and possesses potent activity against breast cancer growth and metastasis, which could be potentially developed as a lead candidate against breast cancers with elevated Src tyrosine kinase activity.

• Synthesis and biological evaluation of novel triptolide analogues for anticancer activity.

  Authors: Bing Zhou, Zehong Miao, Gang Deng, Jian Ding, Yaxi Yang, Huijin Feng, Yuanchao Li

  Bioorganic & medicinal chemistry letters. 11/2010; 20(21):6217-21.

  Three types of novel triptolide analogues with 9,11-olefin (3-5), five-membered unsaturated lactam ring (6-7) or A/B cis ring junction (8-14) were synthesized. Although with 9,11-olefin instead ofThree types of novel triptolide analogues with 9,11-olefin (3-5), five-membered unsaturated lactam ring (6-7) or A/B cis ring junction (8-14) were synthesized. Although with 9,11-olefin instead of 9,11-β-epoxide, compound 4a was much more active than the parent natural triptolide (1) with the lowest IC(50) value of 0.05nM for SKOV-3 cells, clearly challenging the traditional viewpoint on the necessity of 9,11-β-epoxide group of triptolide. In addition, structure-activity relationships for three classes of compounds were studied.