BeiGene Beijing Co.

Beijing, China

BeiGene Beijing Co.

Beijing, China
SEARCH FILTERS
Time filter
Source Type

Lin X.,China National Institute of Biological Sciences | Lin X.,Beijing Normal University | Huang X.-P.,University of North Carolina at Chapel Hill | Chen G.,BeiGene Beijing Co. | And 8 more authors.
Journal of Medicinal Chemistry | Year: 2012

Of great interest in recent years has been computationally predicting the novel polypharmacology of drug molecules. Here, we applied an "induced-fit†protocol to improve the homology models of 5-HT 2A receptor, and we assessed the quality of these models in retrospective virtual screening. Subsequently, we computationally screened the FDA approved drug molecules against the best induced-fit 5-HT 2A models and chose six top scoring hits for experimental assays. Surprisingly, one well-known kinase inhibitor, sorafenib, has shown unexpected promiscuous 5-HTRs binding affinities, K i = 1959, 56, and 417 nM against 5-HT 2A, 5-HT 2B, and 5-HT 2C, respectively. Our preliminary SAR exploration supports the predicted binding mode and further suggests sorafenib to be a novel lead compound for 5HTR ligand discovery. Although it has been well-known that sorafenib produces anticancer effects through targeting multiple kinases, carefully designed experimental studies are desirable to fully understand whether its "off-target†5-HTR binding activities contribute to its therapeutic efficacy or otherwise undesirable side effects. © 2012 American Chemical Society.


Zhu Y.,Peking University | Tian T.,Peking University | Li Z.,Peking University | Tang Z.,BeiGene Beijing Co. | And 8 more authors.
Scientific Reports | Year: 2015

The patient-derived tumor xenograft (PDTX) model has become the most realistic model for preclinical studies. PDTX models of gastric cancer using surgical tissues are reported occasionally; however, the PDTX models using gastroscopic biopsies, which are best for evaluating new drugs, are unreported. In our study, a total of 185 fresh gastroscopic biopsies of gastric cancer were subcutaneously transplanted into NOD/SCID (Nonobese Diabetic/Severe Combined Immunodeficiency) mice. Sixty-three PDTX models were successfully established (34.1%, 63/185) and passaged to maintain tumors in vivo, and the mean latency period of xenografts was 65.86 ± 32.84 days (11-160 days). Biopsies of prior chemotherapy had a higher transplantation rate (52.1%, 37/71) than biopsies after chemotherapy (21.9%, 25/114; P = 0.000). No differences were found between the latency period of xenografts and characteristics of patients. The pathological and molecular features of PDTX as well as chemosensitivity were highly consistent with those of primary tumors of patients. The genetic characteristics were stable during passaging of PDTX models. In summary PDTX models using gastroscopic biopsies in gastric cancer were demonstrated for the first time, and the biological characteristics of the PDTX models were highly consistent with patients, which provided the best preclinical study platform for gastric cancer. © 2015, Nature Publishing Group. All rights reserved.


PubMed | MyGenostics Inc. Beijing, Peking University and BeiGene Beijing Co.
Type: | Journal: Scientific reports | Year: 2015

The patient-derived tumor xenograft (PDTX) model has become the most realistic model for preclinical studies. PDTX models of gastric cancer using surgical tissues are reported occasionally; however, the PDTX models using gastroscopic biopsies, which are best for evaluating new drugs, are unreported. In our study, a total of 185 fresh gastroscopic biopsies of gastric cancer were subcutaneously transplanted into NOD/SCID (Nonobese Diabetic/Severe Combined Immunodeficiency) mice. Sixty-three PDTX models were successfully established (34.1%, 63/185) and passaged to maintain tumors in vivo, and the mean latency period of xenografts was 65.86 32.84 days (11-160 days). Biopsies of prior chemotherapy had a higher transplantation rate (52.1%, 37/71) than biopsies after chemotherapy (21.9%, 25/114; P = 0.000). No differences were found between the latency period of xenografts and characteristics of patients. The pathological and molecular features of PDTX as well as chemosensitivity were highly consistent with those of primary tumors of patients. The genetic characteristics were stable during passaging of PDTX models. In summary PDTX models using gastroscopic biopsies in gastric cancer were demonstrated for the first time, and the biological characteristics of the PDTX models were highly consistent with patients, which provided the best preclinical study platform for gastric cancer.


Liu Z.,General Hospital of PLA | Zhang Q.,Sichuan University | Peng H.,BeiGene Beijing Co. | Zhang W.-Z.,General Hospital of PLA
Applied Biochemistry and Biotechnology | Year: 2012

Lectins, a group of carbohydrate-binding proteins ubiquitously distributed into plants and animals, are well-known to have astonishing numerous links to human cancers. In this review, we present a brief outline of the representative animal lectins such as galectins, C-type lectins, and annexins by targeting programmed cell death (or apoptosis) pathways, and also summarize these representative lectins as possible anti-cancer drug targets. Taken together, these inspiring findings would provide a comprehensive perspective for further elucidating the multifaceted roles of animal lectins in apoptosis pathways of cancer, which, in turn, may ultimately help us to exploit lectins for their therapeutic purposes in future drug discovery. © Springer Science+Business Media, LLC 2012.


Liu Z.,General Hospital of PLA | Ouyang L.,University of Sichuan | Peng H.,BeiGene Beijing Co. | Zhang W.-Z.,General Hospital of PLA
Cell Proliferation | Year: 2012

Oridonin, an active diterpenoid isolated from traditional Chinese herbal medicine, has drawn rising attention for its remarkable apoptosis- and autophagy-inducing activity and relevant molecular mechanisms in cancer therapy. Apoptosis is a well known type of cell death, whereas autophagy can play either pro-survival or pro-death roles in cancer cells. Accumulating evidence has recently revealed relationships between apoptosis and autophagy induced by oridonin; however, molecular mechanisms behind them remain to be discovered. In this review, we focus on highlighting updated research on oridonin-induced cell death signalling pathways implicated in apoptosis and autophagy, in many types of cancer. In addition, we further discuss cross-talk between apoptosis and autophagy induced by oridonin, in cancer. Taken together, these findings open new perspectives for further exploring oridonin as a potential anti-tumour agent targeting apoptosis and autophagy, in future anti-cancer therapeutics. © 2012 Blackwell Publishing Ltd.


Lu W.,Soochow University of China | Geng D.,Soochow University of China | Sun Z.,BeiGene Beijing Co. | Yang Z.,Soochow University of China | And 3 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2014

The hedgehog (Hh) signaling pathway is a key regulator during embryonic development, while in adults, it has limited functions such as stem cell maintenance and tissue repair. The aberrant activity of the Hh signaling in adults has been linked to numerous human cancers. Inhibition of Hh signaling therefore represents a promising approach toward novel anticancer therapies. The Smoothened (Smo) receptor mediates Hh signaling. Here we report a new series of Smo antagonists which were obtained by a scaffold hopping strategy. Compounds from this new scaffold demonstrated decent inhibition of Hh pathway signaling. The new scaffold can serve as a starting point for further optimization. © 2014 Elsevier Ltd. All rights reserved.


PubMed | BeiGene Beijing Co. and Soochow University of China
Type: Journal Article | Journal: Bioorganic & medicinal chemistry | Year: 2015

The Wnt signaling pathway is a pivotal developmental pathway. It operates through control of cellular functions such as proliferation, differentiation, migration and polarity. Aberrant Wnt signaling has been implicated in the formation and metastasis of tumors. Porcupine is a component of the Wnt signaling pathway. It is a member of the membrane-bound O-acyltransferase family of proteins. Porcupine catalyzes the palmitoylation of Wnt proteins, a process which is essential to their secretion and activity. Here we report a novel series of compounds obtained by a scaffold hybridization strategy from two known porcupine inhibitor classes. The leading compound 62 demonstrated subnanomolar (IC50 0.11 nM) inhibition of Wnt signaling in a paracrine cellular reporter gene assay. Compound 62 also potently inhibited Wnt secretion into culture medium, an indication of direct inhibition of the porcupine protein. Furthermore, compound 62 showed excellent chemical, plasma and liver microsomal stabilities. Collectively, these results strongly support further optimization of this novel scaffold to develop better Wnt pathway inhibitors.


PubMed | BeiGene Beijing Co. and Soochow University of China
Type: | Journal: European journal of medicinal chemistry | Year: 2016

The Wnt signaling pathway is a critical developmental pathway which operates through control of cellular functions such as proliferation and differentiation. Aberrant Wnt signaling has been linked to the formation and metastasis of tumors. Porcupine, a member of the membrane-bound O-acyltransferase family of proteins, is an important component of the Wnt pathway. Porcupine catalyzes the palmitoylation of Wnt proteins, a process needed for their secretion and activity. Here we report a novel series of compounds obtained by a scaffold hybridization strategy from a known porcupine inhibitor class. The leading compound 59 demonstrated subnanomolar inhibition of Wnt signaling in a paracrine cellular assay. Compound 59 also showed excellent chemical, plasma and liver microsomal stabilities. Furthermore, compound 59 exhibited good pharmacokinetic profiles with 30% oral bioavailability in rat. Collectively, these results strongly support further optimization of this novel scaffold to develop better Wnt pathway inhibitors.


Yao Z.,Sloan Kettering Cancer Center | Torres N.M.,Sloan Kettering Cancer Center | Tao A.,New York University | Gao Y.,Sloan Kettering Cancer Center | And 7 more authors.
Cancer Cell | Year: 2015

ERK signaling requires RAS-induced RAF dimerization and is limited by feedback. Activated BRAF mutants evade feedback inhibition of RAS by either of two mechanisms. BRAF V600 mutants are activated monomers when RAS activity is low; all other activating BRAF mutants function as constitutive RAS-independent dimers. RAF inhibitors effectively inhibit mutant monomers, but not dimers; their binding to one site in the dimer significantly reduces their affinity for the second. Tumors with non-V600E BRAF mutants are insensitive to these drugs, and increased expression of BRAF V600E dimers causes acquired resistance. A compound that equally inhibits both sites of mutant RAF dimers inhibits tumors driven by either class of mutants or those BRAF V600E tumors with dimer-dependent acquired resistance to monomer-specific inhibitors. © 2015 Elsevier Inc.


Wang Y.,BeiGene Beijing Co. | Mogg R.,Merck And Co. | Lunceford J.,Merck And Co.
Biometrics | Year: 2012

Biomarkers play an increasing role in the clinical development of new therapeutics. Earlier clinical decisions facilitated by biomarkers can lead to reduced costs and duration of drug development. Associations between biomarkers and clinical endpoints are often viewed as initial evidence supporting the intended purpose. As a result, even though it is widely understood that correlation is not proof of a causal relationship, correlation continues to be used as a metric for biomarker qualification in practice. In this article, we introduce a causal correlation framework where two different types of correlations are defined at the individual level. We show that the correlation estimate is a composite of different components, and needs to be interpreted with caution when used for biomarker qualification to avoid misleading conclusions. Otherwise, a significant correlation can be concluded even in the absence of a true underlying association. We also show how the causal quantities of interest are testable in a crossover design and provide discussion on the challenges that exist in a parallel group setting. © 2011, The International Biometric Society.

Loading BeiGene Beijing Co. collaborators
Loading BeiGene Beijing Co. collaborators