Xiongwen Zhang

Targeting Hippo pathway by specific interruption of YAP-TEAD interaction using cyclic YAP-like peptides

Hippo signaling pathway is emerging as a novel target for anticancer therapy because it plays key roles in organ size control and tumorigenesis. As the downstream effectors, Yes‐associated protein (YAP)‐transcriptional enhancer activation domain family member (TEAD) association is essential for YAP‐driven oncogenic activity, while TEAD is largely dispensable for normal tissue growth. We present the design of YAP‐like peptides (17mer) to occupy the interface 3 on TEAD. Introducing cysteines at YAP sites 87 and 96 can induce disulfide formation, as confirmed by crystallography. The engineered peptide significantly improves the potency in disrupting YAP‐TEAD interaction in vitro. To confirm that blocking YAP‐TEAD complex formation by directly targeting on TEAD is a valid approach, we report a significant reduction in tumor growth rate in a hepatocellular carcinoma xenograft model after introducing the dominant‐negative mutation (Y406H) of TEAD1 to abolish YAP‐TEAD interaction. Our results suggest that targeting TEAD is a promising strategy against YAP‐induced oncogenesis.—Zhou, Z., Hu, T., Xu, Z., Lin, Z., Zhang, Z., Feng, T., Zhu, L., Rong, Y., Shen, H., Luk, J. M., Zhang, X., Qin, N. Targeting Hippo pathway by specific interruption of YAP‐TEAD interaction using cyclic YAP‐like peptides. FASEB J. 29, 724‐732 (2015). www.fasebj.org

Design, synthesis and biological evaluation of colchicine derivatives as novel tubulin and histone deacetylase dual inhibitors

A new class of colchicine derivatives were designed and synthesized as tubulin-HDAC dual inhibitors. Biological evaluations of these hybrids included the inhibitory activity of HDAC, tubulin polymerization analysis, inxa0vitro cell cycle analysis in HCT-116 cells and cytotoxicity against different cancer cell lines. Hybrid 6d behaved as potent HDAC-tubulin dual inhibitor and showed comparable cytotoxicity with colchicine. Compound 11a exhibited powerful tubulin inhibitory activity, moderate anti-HDAC activity and the most potent cytotoxicity (IC50xa0=xa02-105xa0nM).

Identification of a Novel Aminotetralin Class of HDAC6 and HDAC8 Selective Inhibitors

Herein we report the identification of a novel class of HDAC6 and HDAC8 selective inhibitors through a unique chemistry and phenotypic screening strategy. Tetrahydroisoquinoline 12 was identified as a potent HDAC6 and HDAC8 dual inhibitor from a focused library through cellular tubulin acetylation and p21 induction screening assays. Scaffold hopping from 12 led to the discovery of an aminotetralin class of HDAC inhibitors. In particular, the 3-R stereoisomer 32 showed highly potent inhibition against HDAC6 and HDAC8 with IC50 values of 50 and 80 nM, respectively. Treatment of neuroblastoma BE(2)C cells with 32 resulted in elevated levels of acetylated tubulin, TrkA, and neurite outgrowth with only marginal effects on p21 induction and histone H3 acetylation. Consistent with its weak enzymatic inhibition of HDAC1, 32 showed significantly less cytotoxicity than SAHA and moderately inhibited the growth of myeloma NCI-H929 and OPM-2 cells.

Receptor-targeting fluorescence imaging and theranostics using a graphene oxide based supramolecular glycocomposite

Intercellular glycoligand-receptor interactions are implicated in a number of disease-related processes. Effective tools that target these receptors may facilitate disease theranostics. However, owing to their low binding affinity, multivalent presentation of glycoligands is needed to increase the avidity with transmembrane receptors. While previous strategies focus on the covalent coupling of glycoligands to a synthetic backbone, we show here that the use of graphene oxide (GO) greatly enhances the cellular and tissue imaging ability of a small-molecule fluorescence glycoprobe. We determine that GO with an optimum size may serve as a clustering platform to reinforce the interaction of the glycoprobe with its selective receptor on a cancer cell. This phenomenon has been consistently observed with the xenograft tissue of a tumor-bearing mouse. Using this principle we have further constructed a supramolecular glycocomposite by co-assembling the glycoprobe and an anticancer drug onto a single GO surface. In addition to imaging ability, this material displays improved toxicity for liver cancer cells that over express the glycoprotein receptor, when compared to the control cells.

The discovery and optimization of novel dual inhibitors of topoisomerase ii and histone deacetylase

A novel class of podophyllotoxin derivatives have been designed and synthesized based on the synergistic antitumor effects of topoisomerase II and histone deacetylase inhibitors. Their inhibitory activities towards histone deacetylases and Topo II and their cytotoxicities in cancer cell lines were evaluated. The aromatic capping group connection, linker length and zinc-binding group were systematically varied and preliminary conclusions regarding structure-activity relationships are discussed. Among all of the synthesized hybrid compounds, compound 24 d showed the most potent HDAC inhibitory activity at a low nanomolar level and exhibited powerful antiproliferative activity towards HCT116 colon carcinoma cells at a low micromolar level. Further exploration of this series led to the discovery of potent dual inhibitor 32, which exhibited the strongest in vitro cytotoxic activity.

Design, Synthesis, and Biological Evaluation of New Cathepsin B-Sensitive Camptothecin Nanoparticles Equipped with a Novel Multifuctional Linker

Traditional antitumor drugs such as camptothecin and paclitaxel derivatives are widely used in cancer chemotherapy. However, the major defects of those agents include severe toxicity and poor water solubility. With these in mind, a novel multifunctional linker was designed and two Cathepsin B (CTB) sensitive CPT conjugates (9a and 9b) were synthesized. Through click chemistry, additional functional group mPEG2000 can be easily introduced into these conjugates. The introduction of mPEG2000 fragment resulted in the formation of nanoparticles 1a and 1b (average particle sizes were 216.9 and 257.9 nm, respectively) with significantly increased water solubility (more than 19u202f000-fold). The release of therapeutic drug SN-38 in the presence of CTB was confirmed by HPLC and prodrug 1a showed potent in vitro cytotoxicity against all tested cell lines. Impressively, compared with irinotecan, CTB sensitive prodrug 1a displayed similar in vivo efficacy with remarkable decreased in vivo toxicity.

MFTZ-1, an actinomycetes subspecies-derived antitumor macrolide, functions as a novel topoisomerase II poison

14-Ethyl-2,5,11-trimethyl-4,13,19,20-tetraoxa-tricyclo[14.2.1.17,10]eicosane-3,12-dione (MFTZ-1), a new macrolide compound isolated from Streptomyces sp. Is9131, displayed wide cytotoxicity in human tumor cell lines with an average IC50 of 0.905 μmol/L. Notably, MFTZ-1 showed significant cytotoxicity in the three multidrug resistance cell lines with an average resistance factor of 2.08. The in vivo experiments showed that MFTZ-1 had inhibitory effects on the human ovarian carcinoma HO-8910 cell line xenotransplanted in nude mice. Further studies showed that MFTZ-1 induced DNA double-strand breaks and triggered mitochondria-dependent apoptosis in human leukemia HL-60 cells. Using a yeast genetic system, we found that topoisomerase (Topo) II rather than Topo I was the primary cellular target of MFTZ-1. Most importantly, MFTZ-1 functions as a novel nonintercalative Topo II poison via binding to ATPase of Topo II, characterized by its strong inhibition on the decatenation and relaxation of Topo II. The capacity of MFTZ-1 to stabilize Topo II–DNA covalent complexes was comparable with that of the classic Topo II poison, etoposide. Moreover, using a Topo II catalytic inhibitor aclarubicin and Topo II–deficient HL-60/MX2 cells, we further showed that MFTZ-1–triggered DNA double-strand breaks and apoptosis occurred in a Topo II–dependent manner. Together, the well-defined Topo II–poisoning function and the potent antitumor activity, with the appreciable anti–multidrug resistance action in particular, promises MFTZ-1 as a novel potential Topo II–targeted agent, which merits further research and development. [Mol Cancer Ther 2007;6(11):3059–70]

Targeting Cadherin-17 Inactivates Ras/Raf/MEK/ERK Signaling and Inhibits Cell Proliferation in Gastric Cancer

Cadherin-17 (CDH17), one member of 7D-cadherin superfamily, was overexpressed in gastric cancer (GC) and was associated with poor survival, tumor recurrence, metastasis, and advanced tumor stage. So far the cellular function and signaling mechanism of CDH17 in GC remains unclear. In this study, we showed that over 66% of GC cell lines (20/30) were CDH17 positive. Tissue microarray (TMA) assay showed that 73.6% Chinese GC tissues (159/216) were CDH17 positive, while 37% respective adjacent normal tissues were CDH17 positive. Knockdown of CDH17 inhibited cell proliferation, migration, adhesion and colony formation, and also induced a cell cycle arrest and apoptosis in AGS human GC cells. On the other side, overexpression of CDH17 facilitated MGC-803 GC tumor growth in nude mice. Antibody array and Western blotting assay demonstrated that knockdown of CDH17 in AGS cells down-regulated integrin β series proteins, further inactivated the Ras/Raf/MEK/ERK pathway and led to p53 and p21 accumulation, which resulted in proliferation inhibition, cell-cycle arrest and apoptosis induction. Collectively, our data firstly demonstrate the capacity of CDH17 to regulate the activity of Ras/Raf/MEK/ERK pathway for cell proliferation in GC, and suggest that CDH17 can serve as an attractive therapeutic target for future research.

Enhanced cellular uptake and intracellular drug controlled release of VESylated gemcitabine prodrug nanocapsules.

Gemcitabine, 2,2-difluoro-2-deoxycytidine (dFdC), is the first-line antitumor agent in the treatment of pancreatic tumors. However, it possesses certain drawbacks, such as poor biological half-life resulted from rapid metabolism and the induction of resistance, leading to its restricted therapeutic potential. With the purpose of overcoming the above drawbacks, we developed a novel VESylated gemcitabine (VES-dFdC) prodrug by coupling the N4-amino group of the pyrimidine ring of dFdC to the carboxylic group of vitamin E succinate (VES). The resulting amphiphilic compound could protect the N4-amino group of the pyrimidine ring of dFdC from being degraded by cytidine deaminase. What is more, the prodrug was able to form nanocapsules in aqueous media (similar to the structure of cytomembrane), confirmed by transmission electron microscope (TEM). Their average particle size is about 107 nm with zeta potential of -33.4 mV measured by dynamic light scattering (DLS). VES-dFdC nanocapsules showed accelerated accumulative drug release profile in simulated lysosome environment (sodium acetate buffer pH 5+cathepsin B, an enzyme in lysosome), due to the easily hydrolyzed property of amide bond by cathepsin B, while rather stable in PBS (pH 7.4) or sodium acetate buffer (pH 5.0) without cathepsin B, indicating their enhanced intracellular drug controlled release manner. Besides, VES-dFdC prodrug nanocapsules showed enhanced cellular uptake ability, and the amount of cellular uptake of the nanocapsules by the pancreatic cancer cell line BxPC-3 is seventy times higher than that of native gemcitabine in the first 1.5 h. Compared with free gemcitabine, VES-dFdC nanocapsules showed essentially increased growth inhibition activity against BxPC-3 cells, indicating its great potential as prodrug for pancreatic tumor therapy with improved antitumor activity.

Targeting NEK2 as a promising therapeutic approach for cancer treatment.

ABSTRACT Never in Mitosis (NIMA) Related Kinase 2 (NEK2) plays a key role in regulating mitotic processes, including centrosome duplication and separation, microtubule stabilization, kinetochore attachment and spindle assembly checkpoint. NEK2 is aberrantly overexpressed in a wide variety of human cancers and has been implicated in various aspects of malignant transformation, including tumorigenesis, drug resistance and tumor progression. The close relationship between NEK2 and cancer has made it an attractive target for anticancer therapeutic development; however, the mechanisms of how NEK2 coordinates altered signaling to malignant transformation remains unclear. In this paper, we discuss the functional roles of NEK2 in cancer development; highlight some of the significant NEK2 signaling in cancer, and summarize recent advances in the development of NEK2 inhibitors.