AST1306, A Novel Irreversible Inhibitor of the Epidermal Growth Factor Receptor 1 and 2, Exhibits Antitumor Activity Both In Vitro and In Vivo

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 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/Nneu 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

Anisotropic Elastoplastic Damage Mechanics Method to Predict Fatigue Life of the Structure

New damage mechanics method is proposed to predict the low-cycle fatigue life of metallic structures under multiaxial loading. The microstructure mechanical model is proposed to simulate anisotropic elastoplastic damage evolution. As the micromodel depends on few material parameters, the present method is very concise and suitable for engineering application. The material parameters in damage evolution equation are determined by fatigue experimental data of standard specimens. By employing further development on the ANSYS platform, the anisotropic elastoplastic damage mechanics-finite element method is developed. The fatigue crack propagation life of satellite structure is predicted using the present method and the computational results comply with the experimental data very well

Geochemistry of the Eocene clastic sediments (Suonahu Formation) in the North Qiangtang Basin, Tibet: implications for paleoclimate conditions, provenance and tectonic setting

The geochemistry of clastic sedimentary units of the Suonahu Formation from the QD17 Well in the northern Qiangtang basin (Tibet) was studied using various chemical analyses. SiO2/Al2O3 ratios value indicate that compositional maturity and recycling of the sediments are low to moderate. The ÎŁREE contents of the clastic sediments range from 29.28 to 191.92 ppm. The REE geochemistry of the clastic sediments suggests that these different lithological samples are derived from a similar terrigenous source and the Eu anomaly was inherited from the source rocks. The paleoclimate index (C-value) varies from 0.01 to 0.36, reflecting generally arid to semiarid conditions. In addition, Rb/Sr (~0.41) and Sr/Cu (~37.02) ratios support the idea that arid conditions prevailed during deposition of the Suonahu Formation. Sr/Ba ratios (0.48- 3.23) suggest a paleoenvironment with variable salinity. The covariation among this factor and paleoclimate indicators suggests that variations in climatic conditions exerted a primary control on salinity. The chemical index of alteration (CIA), A-CN-K ternary diagram, and low Th/U ratios indicate that the parent rocks of the clastic sediments experienced weak chemical weathering. Two multidimensional tectonic discrimination diagrams based on major elements show the Suonahu Formation deposited in a rift-related basin. The TiO2 versus Zr, La/Th versus Hf, and Co/Th versus La/Sc bivariate diagrams and multi-major elements discrimination diagram indicate that the detritus were primarily derived from felsic igneous rocks with less intermediate igneous rocks.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author

Discovery of Novel Disruptor of Silencing Telomeric 1‑Like (DOT1L) Inhibitors using a Target-Specific Scoring Function for the (<i>S</i>)‑Adenosyl‑l‑methionine (SAM)-Dependent Methyltransferase Family

The disruptor of telomeric silencing 1-like (DOT1L) protein is a histone H3K79 methyltransferase that plays a key role in transcriptional elongation and cell cycle regulation and is required for the development and maintenance of MLL-rearranged mixed lineage leukemia. Much effort has been dedicated toward discovering novel scaffold DOT1L inhibitors using different strategies. Here, we report the development and application of a target-specific scoring function, the SAM score, for (<i>S</i>)-adenosyl-l-methionine (SAM)-dependent methyltransferases, for the discovery of novel DOT1L inhibitors. On the basis of the SAM score, we successfully identified a novel class of DOT1L inhibitors with a scaffold of [1,2,4]-triazolo-[3,4-<i>b</i>]­[1,3,4]-thiadiazole, in which compound <b>6</b> exhibits an IC₅₀ value of 8.3 μM with selectivity versus other tested SAM-dependent methyltransferases. In cellular studies, <b>6</b> selectively targets DOT1L, blocks the proliferation of mixed lineage leukemia cell lines, and causes cell cycle arrest and apoptosis. Moreover, we analyzed the putative binding modes of <b>6</b> and its analogues obtained by molecular docking, which may assist with the future development of DOT1L inhibitors with improved potency and selectivity profiles