Discovery of new thienopyrimidine derivatives as potent and orally efficacious phosphoinositide 3-kinase inhibitors.

A series of new thienopyrimidine derivatives has been discovered as potent PI3K inhibitors. The systematic SAR studies for these analogues are described. Among them, 8a and 9a exhibit nanomolar enzymatic potencies and sub-micromolar cellular anti-proliferative activities. 8a displays favorable pharmacokinetic profiles, while 9a easily undergoes deacetylation to yield a major metabolite 8a. Furthermore, 8a and 9a potently inhibit tumor growth in a dose-dependent manner in the NCI-H460 xenograft model with an acceptable safety profile.

Phase Error Correction for Approximated Observation-Based Compressed Sensing Radar Imaging.

Defocus of the reconstructed image of synthetic aperture radar (SAR) occurs in the presence of the phase error. In this work, a phase error correction method is proposed for compressed sensing (CS) radar imaging based on approximated observation. The proposed method has better image focusing ability with much less memory cost, compared to the conventional approaches, due to the inherent low memory requirement of the approximated observation operator. The one-dimensional (1D) phase error correction for approximated observation-based CS-SAR imaging is first carried out and it can be conveniently applied to the cases of random-frequency waveform and linear frequency modulated (LFM) waveform without any a priori knowledge. The approximated observation operators are obtained by calculating the inverse of Omega-K and chirp scaling algorithms for random-frequency and LFM waveforms, respectively. Furthermore, the 1D phase error model is modified by incorporating a priori knowledge and then a weighted 1D phase error model is proposed, which is capable of correcting two-dimensional (2D) phase error in some cases, where the estimation can be simplified to a 1D problem. Simulation and experimental results validate the effectiveness of the proposed method in the presence of 1D phase error or weighted 1D phase error.

Research on fire early warning index system of coal mine goaf based on multi-parameter fusion.

In order to improve the precision of goaf fire early warning outcomes, this paper obtains the temperature characteristic index of goaf fire early warning by using a coal spontaneous combustion thermogravimetric test and a coal spontaneous combustion programmed heating test. The major gas index and auxiliary gas index for early warning are derived using the integration of the Graham coefficient and grey correlation approach. The D-S evidence theory, which involves optimizing weight allocation, is utilized to integrate the early warning temperature index and various gas indexes. Based on the fusion results, a coal mine goaf fire early warning index system is developed through multi-parameter fusion. The early warning index system is then validated through a programmed heating experiment. The results show that the process of coal spontaneous combustion can be categorized into six distinct stages: latent stage, oxidation stage, critical stage, pyrolysis stage, fission stage, and combustion stage. These stages are determined by the characteristic temperatures of coal spontaneous combustion, which are 31.7 °C, 54.8 °C, 153.7 °C, 204.5 °C, and 241.6 °C. The major gas index for early warning of goaf fires can be determined by 100∆(CO)/∆O2(%). Additionally, auxiliary gas indexes such as C3H8/CH4, C3H8/C2H6, C2H4/C2H6, and C2H2 can be used for goaf fire early warning. The programmed heating experiment shows that the early warning system software is designed by the multi-parameter fusion goaf fire early warning index system is accurate and effective. The selection of the goaf fire early warning index is more rational and precise when using the multi-parameter fusion goaf fire early warning index system based on the D-S evidence theory of weight allocation. It offers robust support for enhancing the goaf fire early warning index system and predicting coal mine goaf fires.

A novel PI3K/mTOR dual inhibitor XH002 exhibited robust antitumor activity in NSCLC.

NSCLC is a worldwide challenge due to its high incidence and poor survival. PI3K-Akt-mTOR (PAM) pathway is one of the major pathways that mediate receptor tyrosine kinases (RTKs) signalling transduction. Aberration in PAM pathway is indicated correlating with poor prognosis of NSCLC. In this article, we highlighted a 2-amino-4-methylquinazoline derivative XH002 as PI3K/mTOR dual inhibitor with outstanding antitumor efficacy. Briefly, XH002 significantly repressed proliferation of PI3KCA mutant and/or P-S6RP, P-RAS40 high expressed NSCLC cells. In vitro, XH002 decreased the phosphorylation of PAM pathway proteins in a dose-dependent and time-dependent way. Further investigation indicated that the cancer cells repression by XH002 derived from inducing cell cycle arrest in G1 phase. Moreover, XH002 remarkably inhibited tumour growth of EGFR-TKIs resistant NCI-H1975 xenograft model by blocking PAM pathway. In conclusion, XH002 is a potent oral PI3K/mTOR dual inhibitor that possesses excellent antitumor efficacy against PIK3CA mutant NSCLC, including which resistant to EGFR-TKIs treatments.

Discovery and Optimization of 2-Amino-4-methylquinazoline Derivatives as Highly Potent Phosphatidylinositol 3-Kinase Inhibitors for Cancer Treatment.

Increased phosphatidylinositol 3-kinase (PI3K) signaling is among the most common alterations in cancer, spurring intensive efforts to develop new cancer therapeutics that target this pathway. In this work, we discovered a series of novel 2-amino-4-methylquinazoline derivatives through a hybridization and subsequent scaffold hopping approach that were highly potent class I PI3K inhibitors. Lead optimization resulted in several promising compounds (e.g., 19, 20, 37, and 43) with nanomolar PI3K potencies, prominent antiproliferative activities, favorable PK profiles, and robust in vivo antitumor efficacies. More interestingly, compared with 19 and 20, 37 and 43 demonstrated improved brain penetration and in vivo efficacy in an orthotopic glioblastoma xenograft model. Furthermore, preliminary safety assessments including hERG channel inhibition, AMES, CYP450 inhibition, and single-dose toxicity were performed to characterize their toxicological properties.

Tetrahydrocurcumin induces G2/M cell cycle arrest and apoptosis involving p38 MAPK activation in human breast cancer cells.

Curcumin (CUR) is a major naturally-occurring polyphenol of Curcuma species, which is commonly used as a yellow coloring and flavoring agent in foods. In recent years, it has been reported that CUR exhibits significant anti-tumor activity in vivo. However, the pharmacokinetic features of CUR have indicated poor oral bioavailability, which may be related to its extensive metabolism. The CUR metabolites might be responsible for the antitumor pharmacological effects in vivo. Tetrahydrocurcumin (THC) is one of the major metabolites of CUR. In the present study, we examined the efficacy and associated mechanism of action of THC in human breast cancer MCF-7 cells for the first time. Here, THC exhibited significant cell growth inhibition by inducing MCF-7 cells to undergo mitochondrial apoptosis and G2/M arrest. Moreover, co-treatment of MCF-7 cells with THC and p38 MAPK inhibitor, SB203580, effectively reversed the dissipation in mitochondrial membrane potential (Δψm), and blocked THC-mediated Bax up-regulation, Bcl-2 down-regulation, caspase-3 activation as well as p21 up-regulation, suggesting p38 MAPK might mediate THC-induced apoptosis and G2/M arrest. Taken together, these results indicate THC might be an active antitumor form of CUR in vivo, and it might be selected as a potentially effective agent for treatment of human breast cancer.