Discovery of a Long Half-Life AURKA Inhibitor to Treat MYC-Amplified Solid Tumors as a Monotherapy and in Combination with Everolimus.

Aurora kinase inhibitors, such as alisertib, can destabilize MYC-family oncoproteins and have demonstrated compelling antitumor efficacy. In this study, we report 6K465, a novel pyrimidine-based Aurora A inhibitor, that reduces levels of c-MYC and N-MYC oncoproteins more potently than alisertib. In an analysis of the antiproliferative effect of 6K465, the sensitivities of small cell lung cancer (SCLC) and breast cancer cell lines to 6K465 were strongly associated with the protein levels of c-MYC and/or N-MYC.

Modulating the affinity and signaling bias of cannabinoid receptor 1 antagonists.

Cannabinoid receptor 1 (CB1) is a G protein-coupled receptor and a therapeutic target for metabolic disorders. Numerous CB1 antagonists have been developed, but their functional selectivities and bias towards G protein or β-arrestin signaling have not been systemically characterized. In this study, we analyzed the binding affinities and downstream signaling of two series of pyrazole derivatives bearing 1-aminopiperidine (Series I) or 4-aminothiomorpholine 1,1-dioxide (Series II) moieties, as well as the well-known CB1 antagonists rimonabant and taranabant.

Transcriptome Analysis Reveals the Senescence Process Controlling the Flower Opening and Closure Rhythm in the Waterlilies ( L.).

Most waterlily flowers open at dawn and close after noon usually for three to four days, and thereafter wilt. The short lifespan of flowers restricts the development of the flower postharvest industry. The termination of flower movements is a key event during flower aging process.

Discovery and Synthesis of a Pyrimidine-Based Aurora Kinase Inhibitor to Reduce Levels of MYC Oncoproteins.

The A-type Aurora kinase is upregulated in many human cancers, and it stabilizes MYC-family oncoproteins, which have long been considered an undruggable target. Here, we describe the design and synthesis of a series of pyrimidine-based derivatives able to inhibit Aurora A kinase activity and reduce levels of cMYC and MYCN. Through structure-based drug design of a small molecule that induces the DFG-out conformation of Aurora A kinase, lead compound was identified, which potently (IC < 200 nM) inhibited the proliferation of high-MYC expressing small-cell lung cancer (SCLC) cell lines.

UM171 promotes expansion of autologous peripheral blood hematopoietic stem cells from poorly mobilizing lymphoma patients.

Background: Autologous hematopoietic stem cell transplantation is an effective therapeutic strategy for lymphoma patients. However, some patients have to give up receiving transplantation because of failing to obtain sufficient CD34 cells yields. Therefore, we ex vivo expanded HSCs of lymphoma patients using UM171 to solve the problem of HSCs deficiency.

Hydride-induced anionic cyclization: an efficient method for the synthesis of 6-H-phenanthridines via a transition-metal-free process.

A novel procedure for hydride-induced anionic cyclization has been developed. It includes the reduction of a biaryl bromo-nitrile with a nucleophilic aromatic substitution (S(N)Ar). A range of polysubstituted 6-H-phenanthridines were so obtained in moderate to good yield with good substrate tolerance.

Synthesis of polysubstituted phenanthridines via ligand-free copper-catalyzed annulation.

A novel procedure for the cascade reaction of the addition of a Grignard reagent to a nitrile with a copper-catalyzed C-N bond coupling was developed, which afforded various polysubstituted phenanthridines in moderate to good yields with tolerance for a wide variety of substrates. Experimental data demonstrated that the reaction proceeded more likely through a Cu(I/III) catalytic cycle.

A new protein A assay based on Raman reporter labeled immunogold nanoparticles.

A unique, sensitive, highly specific, and photobleaching-resistant immunoassay system utilizing gold nanoparticles and surface-enhanced Raman scattering (SERS) is described. This new system, featuring a capability of bifunctional analysis, is manufactured by chemisorption of antibody immunoglobulin G (IgG) on gold nanoparticles (AuNP), followed by coupling the Raman-active reporter molecule, 5,5'-dithiobis(2-nitrobenzoic acid) (DTNB) to the surface of IgG-AuNP. The adsorbed DTNB molecules exhibit strong Raman signals via both electromagnetic and chemical enhancement.

Combinatorial computational approaches to identify tetracycline derivatives as flavivirus inhibitors.

Limited structural information of drug targets, cellular toxicity possessed by lead compounds, and large amounts of potential leads are the major issues facing the design-oriented approach of discovering new leads. In an attempt to tackle these issues, we have developed a process of virtual screening based on the observation that conformational rearrangements of the dengue virus envelope protein are essential for the mediation of viral entry into host cells via membrane fusion. Screening was based solely on the structural information of the Dengue virus envelope protein and was focused on a target site that is presumably important for the conformational rearrangements necessary for viral entry.