Qian Zhao

Inhibition of mutant IDH1 is being evaluated clinically as a promising treatment option for various cancers with hotspot mutation at Arg132. Having identified an allosteric, induced pocket of IDH1R132H, we have explored 3-pyrimidin-4-yl-oxazolidin-2-ones as mutant IDH1 inhibitors for in vivo modulation of 2-HG production and potential brain penetration. We report here optimization efforts toward the identification of clinical candidate IDH305 (13), a potent and selective mutant IDH1 inhibitor that has demonstrated brain exposure in rodents. Preclinical characterization of this compound exhibited in vivo correlation of 2-HG reduction and efficacy in a patient-derived IDH1 mutant xenograft tumor model. IDH305 (13) has progressed into human clinical trials for the treatment of cancers with IDH1 mutation.

The pathogenesis of gastric cancer is not completely understood. Tumor necrosis factor-α-induced protein-8 like-2 (TIPE2) has recently been identified as a novel negative regulator gene of the immune system, and studies in mice and humans have suggested its inhibitory action in both inflammation and cancer. In this study, we examined the expression levels of TIPE2 in human gastric cancer tissues and also samples of paraneoplastic control tissue, and found that TIPE2 expression was reduced in gastric cancer. To investigate the role of TIPE2 in gastric cell carcinogenesis, a TIPE2 plasmid was introduced into gastric cell lines and TIPE2 function was examined. Colony-forming assays showed that restoration of TIPE2 expression in gastric cells significantly suppressed cell proliferation. Analysis by flow cytometry showed that the number of cells in the S phase of the cell cycle was reduced concomitant with TIPE2 expression, and cell apoptosis was maintained at a low level. Microarray and western blot analyses revealed that TIPE2 selectively up-regulated N-ras and p27 expression. The role of p27 in mediating TIPE2-associated cell growth inhibition was verified by a p27 siRNA interference assay. In this study, we proved that TIPE2 is an inhibitor of gastric cancer cell growth, and suggest that TIPE2 might promote a p27-associated signaling cascade that leads to restored control of the cell cycle and cell division. Our results provide a new molecular mechanism by which TIPE2 may regulate proliferation of gastric cells.

Hypoxia is an important cause of myocardial cell loss, further inducing various heart illnesses, including acute myocardial infraction (AMI). Long non-coding RNA (LncRNA) discrimination antagonising non-protein coding RNA (DANCR) was firstly identified as epidermal cell differentiation suppressor. Here, we aimed to explore the effects and mechanism of DNACR in hypoxia-induced H9c2 cells. Hypoxic cells were made through 94% N2, 5% CO2, and 1% O2 environment for 24 h. Cell viability and apoptosis were detected via methyl thiazolyl tetrazolium (MTT) method and flow cytometry analysis, respectively. The expression of DANCR and HIF-1α was examined via qRT-PCR. The expression of proteins related to cell apoptosis and PI3K/AKT/mTOR and ERK1/2 signal pathways was examined through western blot analysis. We found that hypoxia induced obvious cell activity inhibition and apoptosis increasing in H9c2 cells. DANCR was negatively regulated under hypoxia condition. Overexpression of DANCR rescued activity and attenuated apoptosis. Moreover, the overexpression of DANCR elevated the activation of PI3K/AKT/mTOR and ERK1/2 pathways. Further study indicated that DANCR could up-regulate the expression of HIF-1α. Si-HIF-1α transfection could remove the beneficial effects of DANCR overexpression in hypoxia-caused H9c2 cells damage. In conclusion, DANCR alleviated hypoxia-caused H9c2 cells damage through positive regulation of HIF-1α.