Sundia MediTech

Shanghai, China

Sundia MediTech

Shanghai, China

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PubMed | Sundia MediTech, Xcovery LLC, Instituto G Gaslini and Irccs Azienda Ospedaliera San Martino Ist Instituto Nazionale Per La Ricerca Sul Cancro
Type: Journal Article | Journal: Oncotarget | Year: 2015

Many different aberrations in the Anaplastic Lymphoma Kinase (ALK) were found to be oncogenic drivers in several cancers including neuroblastoma (NB), therefore ALK is now considered a critical player in NB oncogenesis and a promising therapeutic target. The ALK-inhibitor crizotinib has a limited activity against the various ALK mutations identified in NB patients. We tested: the activity of the novel ALK-inhibitor X-396 administered alone or in combination with Targeted Liposomes carrying ALK-siRNAs (TL[ALK-siRNA]) that are active irrespective of ALK gene mutational status; the pharmacokinetic profiles and the biodistribution of X-396; the efficacy of X-396 versus crizotinib treatment in NB xenografts; whether the combination of X-396 with the TL[ALK-siRNA] could promote long-term survival in NB mouse models. X-396 revealed good bioavailability, moderate half-life, high mean plasma and tumor concentrations. X-396 was more effective than crizotinib in inhibiting in vitro cell proliferation of NB cells and in reducing tumor volume in subcutaneous NB models in a dose-dependent manner. In orthotopic NB xenografts, X-396 significantly increased life span independently of the ALK mutation status. In combination studies, all effects were significantly improved in the mice treated with TL[ALK-siRNA] and X-396 compared to mice receiving the single agents. Our findings provide a rational basis to design innovative molecular-based treatment combinations for clinical application in ALK-driven NB tumors.

Meng L.,Fudan University | Shu M.,Shanghai JiaoTong University | Chen Y.,Fudan University | Yang D.,Sundia MediTech | And 5 more authors.
Cancer Biology and Therapy | Year: 2014

The anaplastic lymphoma kinase (ALK) and the c-Met receptor tyrosine kinase play essential roles in the pathogenesis in multiple human cancers and present emerging targets for cancer treatment. Here, we describe CM-118, a novel lead compound displaying low nanomolar biochemical potency against both ALK and c-Met with selectivity over >90 human kinases. CM-118 potently abrogated hepatocyte growth factor (HGF)-induced c-Met phosphorylation and cell migration, phosphorylation of ALK, EML4-ALK, and ALK resistance mutants in transfected cells. CM-118 inhibited proliferation and/or induced apoptosis in multiple c-Met- and ALK-addicted cancer lines with dose response profile correlating target blockade. We show that the CM-118-induced apoptosis in c-Met-amplified H1993 NSCLC cells involved a rapid suppression of c-Met activity and c-Met-to-EGFR cross-talk, and was profoundly potentiated by EGFR inhibitors as shown by the increased levels of apoptotic proteins cleaved-PARP and Bim as well as reduction of the survival protein Mcl-1. Bim-knockdown or Mcl-1 overexpression each significantly attenuated apoptosis. We also revealed a key role by mTOR in mediating CM-118 action against the EML4-ALK-dependent NSCLC cells. Abrogation of EML4-ALK in H2228 cells profoundly reduced signaling capacity of the rapamycin-sensitive mTOR pathway leading to G1 cell cycle arrest and mitochondrial hyperpolarization, a metabolic perturbation linked to mTOR inhibition. Depletion of mTOR or mTORC1 inhibited H2228 cell growth, and mTOR inhibitors potentiated CM-118's antitumor activity in vitro and in vivo. Oral administration of CM-118 at a wide range of well tolerated dosages diminished c-Met- and ALK phosphorylation in vivo, and caused tumor regression or growth inhibition in multiple c-Met- and ALK-dependent tumor xenografts in mice. CM-118 exhibits favorable pharmacokinetic and drug metabolism properties hence presents a candidate for clinical evaluation. © 2014 Landes Bioscience.

Chen A.,Central China Normal University | Bao Y.,Sundia MediTech | Ge X.,Central China Normal University | Shin Y.,Pacific Northwest National Laboratory | And 2 more authors.
RSC Advances | Year: 2012

Phosphorylated p53 at serine 15 (phospho-p5315) is a potential biomarker of gamma-radiation exposure. In this paper, we described a new magnetic particle (MP)-based electrochemical immunoassay of human phospho-p5315 using carbon nanospheres (NS) and protein cage nanoparticles (PCN) for signal amplification. Greatly enhanced sensitivity was achieved for three reasons: 1) PCN and the p5315 signal antibody (p5315 Ab2) are linked to the carbon NS (PCN-p53 15 Ab2-NS) as a label; 2) PCN increases the amount of metal ions in the cavity of each apoferritin; 3) MPs capture a large amount of primary antibodies. Protein cage templated metallic phosphates, instead of enzymes, as multi-labels have the advantage of eliminating the addition of mediator or immunoreagents and, thus, makes the immunoassay system simpler. Subsequent stripping voltametric analysis, detected olead ions on a disposable screen-printed electrode. The response current was proportional to the phospho-p5315 concentration in the range of 0.02 to 20 ng mL -1 with a detection limit of 0.01 ng mL-1, which was 30-fold lower than that of the ELISA measurement of phospho-p5315. This method shows an acceptable stability and reproducibility and the assay results for phospho-p5315-spiked human serum presented good recovery rates. © 2012 The Royal Society of Chemistry.

Popovici-Muller J.,Agios Pharmaceuticals | Saunders J.O.,Ember Therapeutics | Salituro F.G.,SAGE Therapeutics | Travins J.M.,Agios Pharmaceuticals | And 15 more authors.
ACS Medicinal Chemistry Letters | Year: 2012

Optimization of a series of R132H IDH1 inhibitors from a high throughput screen led to the first potent molecules that show robust tumor 2-HG inhibition in a xenograft model. Compound 35 shows good potency in the U87 R132H cell based assay and ∼90% tumor 2-HG inhibition in the corresponding mouse xenograft model following BID dosing. The magnitude and duration of tumor 2-HG inhibition correlates with free plasma concentration. © 2012 American Chemical Society.

Bao Y.,Sundia MediTech | Wang Q.,Suzhou Kangrun Pharmaceutical Testing Service Inc. | Tang P.,Suzhou Kangrun Pharmaceutical Testing Service Inc.
Journal of Mass Spectrometry | Year: 2013

A novel, rapid and sensitive liquid chromatography/quadrupole linear ion trap mass spectrometry [LC-ESI-(QqLIT)MS/MS] method was developed and validated for the quantification of protopanaxadiol (PPD) in rat plasma. Oleanolic acid (OA) was used as internal standard (IS). A simple protein precipitation based on acetonitrile (ACN) was employed. Chromatographic separation was performed on a Sepax GP-C18 column (50 × 2.1 mm, 5 μM) with a mobile phase consisting of ACN-water and 1.5 μM formic acid and 25 mM lithium acetate (90: 10, v/v) at a flow rate of 0.4 ml/min for 3.0 min. Multiple-reaction-monitoring mode was performed using lithium adduct ion as precursor ion of m/z 467.5/449.4 and 455.6/407.4 for the drug and IS, respectively. Calibration curve was recovered over a concentration range of 0.5-100 ng/ml with a correlation coefficient >0.99. The limit of detection was 0.2 ng/ml in rat plasma for PPD. The results of the intraday and interday precision and accuracy studies were well within the acceptable limits. The validated method was successfully applied to investigate the pharmacokinetic study of PPD after intravenous and gavage administration to rat. Copyright © 2013 John Wiley & Sons, Ltd.

Karasawa H.,University of California at Los Angeles | Pietra C.,Helsinn SA Lugano | Giuliano C.,Helsinn SA Lugano | Garcia-Rubio S.,Helsinn Therapeutics U.S. Inc. | And 4 more authors.
Neurogastroenterology and Motility | Year: 2014

Background: Constipation and L-dopa-induced gastric dysmotility are common gastrointestinal (GI) symptoms in Parkinson's disease (PD). We investigated the novel ghrelin agonist, HM01 influence on GI motor dysfunctions in 6-hydroxydopamine (6-OHDA) rats. Methods: HM01 pharmacological profiles were determined in vitro and in vivo in rats. We assessed changes in fecal output and water content, and gastric emptying (GE) in 6-OHDA rats treated with orogastric (og) HM01 and L-dopa/carbidopa (LD/CD, 20/2 mg/kg). Fos immunoreactivity (ir) cells in specific brain and lumbosacral spinal cord were quantified. Key Results: HM01 displayed a high binding affinity to ghrelin receptor (Ki: 1.42 ± 0.36 nM), 4.3 ± 1.0 h half-life and high brain/plasma ratio. 6-OHDA rats had reduced daily fecal output (22%) and water intake (23%) compared to controls. HM01 (3 and 10 mg/kg) similarly reversed the decreased 4-h fecal weight and water content in 6-OHDA rats. Basal GE was not modified in 6-OHDA rats, however, LD/CD (once or daily for 8 days) delayed GE in 6-OHDA and control rats that was prevented by HM01 (3 mg/kg acute or daily before LD/CD). HM01 increased Fos-ir cell number in the area postrema, arcuate nucleus, nucleus tractus solitarius, and lumbosacral intermediolateral column of 6-OHDA rats where 6-OHDA had a lowering effect compared to controls. Conclusions & Inferences: 6-OHDA rats display constipation- and adipsia-like features of PD and L-dopa-inhibited GE. The new orally active ghrelin agonist, HM01 crosses the blood-brain barrier and alleviates these alterations suggesting a potential benefit for PD with GI disorders. © 2014 John Wiley & Sons Ltd.

Zhao C.,Texas A&M University | Zhao C.,Sundia MediTech | Mitchell T.A.,Texas A&M University | Mitchell T.A.,Illinois State University | And 3 more authors.
Journal of the American Chemical Society | Year: 2012

The ZnCl 2-mediated tandem Mukaiyama aldol lactonization (TMAL) reaction of aldehydes and thiopyridyl ketene acetals provides a versatile, highly diastereoselective approach to trans-1,2-disubstituted β-lactones. Mechanistic and theoretical studies described herein demonstrate that both the efficiency of this process and the high diastereoselectivity are highly dependent upon the type of ketene acetal employed but independent of ketene acetal geometry. Significantly, we propose a novel and distinct mechanistic pathway for the ZnCl 2-mediated TMAL process versus other Mukaiyama aldol reactions based on our experimental evidence to date and further supported by calculations (B3LYP/BSI). Contrary to the commonly invoked mechanistic extremes of [2+2] cycloaddition and aldol lactonization mechanisms, investigations of the TMAL process suggest a concerted but asynchronous transition state between aldehydes and thiopyridyl ketene acetals. These calculations support a boat-like transition state that differs from commonly invoked Mukaiyama "open" or Zimmerman-Traxler "chair-like" transition-state models. Furthermore, experimental studies support the beneficial effect of pre-coordination between ZnCl 2 and thiopyridyl ketene acetals prior to aldehyde addition for optimal reaction rates. Our previously proposed, silylated β-lactone intermediate that led to successful TMAL-based cascade sequences is also supported by the described calculations and ancillary experiments. These findings suggested that a similar TMAL process leading to β-lactones would be possible with an oxopyridyl ketene acetal, and this was confirmed experimentally, leading to a novel TMAL process that proceeds with efficiency comparable to that of the thiopyridyl system. © 2011 American Chemical Society.

Yang J.,Sundia MediTech
Proteomics Research Journal | Year: 2012

The effort to develop better description of protein three-dimensional folding structures has dominated biochemistry and drug discovery research for more than 70 years since Pauling first defined the helical configurations as secondary structure for protein in 1940. The challenge is how to acquire a complete description of protein folding shapes from N-terminal to C-terminal, including regular secondary structure as well as irregular tertiary structure. Here, a novel description method is introduced, which a set of 27 vectors is rigorously derived mathematically from an enclosed space. Each vector represents a three-dimensional folding shape of five successive Cα atoms, and the protein conformation can be completely described along protein backbone. These vectors are expressed by 27 alphabetic symbols, which are called as protein folding shape code (PFSC). Consequently, with PFSC, the folding conformation of any protein with given three-dimensional structure is able to be converted into a simple one-dimensional alphabetic string without gap. Furthermore, to take the advantage of one-dimensional description of folding shapes, the protein conformational structures are able to be compared with Needleman-Wunsch alignment algorithm. The global similarity of protein 3D structures is able to be assessed by a value of protein folding structure alignment score (PFSA-S) as a quantitative measurement, and the similarity and dissimilarity of local structures is able to be examined by alignment table. The results show that this approach has the capability not only to distinguish protein conformers with relatively high similarity, but also to compare proteins with diverse degrees in structural homology. Therefore, this approach provides a consistent procedure, and it produces a unique score for assessment of similarity in protein structure comparison. The significant is that the complete description of protein folding shapes provides a simple and effective means to screen protein database, compare protein structures, search protein fragment and probe drug binding site, study protein mutation and protein misfolding and so on. © 2012 Nova Science Publishers, Inc.

Zeng Y.,Sundia MediTech | Zeng Y.,Shanghai University of Traditional Chinese Medicine | Shao D.,Shanghai University of Traditional Chinese Medicine | Fang Y.,East China Normal University
Analytical Letters | Year: 2011

An on-line two-dimension microflow liquid chromatography was developed for better separation and analysis of the highly complex ingredients of medicinal preparation of traditional Chinese medicine Coptis Chinensis Franch. A two-valve switching system was utilized for two-dimension chromatography with strong cation exchange and reverse-phase capillary columns separation. The components were separated well by this system and yielded over 420 peaks. Under the optimal condition, 4 compounds were detected quantitatively. A good linear relationship was obtained from 0.2μgmL -1 to 24μgmL -1with detection limits (S/N=3) ranging from 0.05μgmL -1 to 0.2μgmL -1for the compounds. We demonstrated that the method can be successfully applied to the analysis of a natural complex sample, with satisfactory results. © Taylor & Francis Group, LLC.

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