Sonrotoclax overcomes BCL2 G101V mutation-induced venetoclax resistance in preclinical models of hematologic malignancy.

Venetoclax, the first-generation inhibitor of the apoptosis regulator B-cell lymphoma 2 (BCL2), disrupts the interaction between BCL2 and proapoptotic proteins, promoting the apoptosis in malignant cells. Venetoclax is the mainstay of therapy for relapsed chronic lymphocytic leukemia and is under investigation in multiple clinical trials for the treatment of various cancers. Although venetoclax treatment can result in high rates of durable remission, relapse has been widely observed, indicating the emergence of drug resistance.

Particulate matter pollution in Kunshan High-Tech zone: Source apportionment with trace elements, plume evolution and its monitoring.

Particulate matter (PM) in the Kunshan High-Tech zone is studied during a three-month campaign. PM and trace elements are measured by the online pollution monitoring, forecast-warning and source term retrieval system AS3. Hourly measured concentrations of PM, PM and 16 trace elements in the PM section (Ca, Pb, Cu, Cl, V, Cr, Fe, Ti, Mn, Ni, Zn, Ga, As, Se, Sr, Ba) are focused.

Crystal structure of human RANKL complexed with its decoy receptor osteoprotegerin.

Receptor activator of NF-κB ligand (RANKL), its signaling receptor RANK, and its decoy receptor osteoprotegerin (OPG) constitute a molecular triad that is critical in regulating bone remodeling, and also plays multiple roles in the immune system. OPG binds RANKL directly to block its interaction with RANK. In this article, we report the 2.

Pharmacokinetics and metabolite identification of a novel VEGFR-2 and Src dual inhibitor 6-chloro-2-methoxy-N-(2-methoxybenzyl) acridin-9-amine in rats by liquid chromatography tandem mass spectrometry.

A novel VEGFR-2 and Src dual inhibitor, 6-Chloro-2-methoxy-N-(2-methoxybenzyl) acridin-9-amine (MBAA), is a 9-aminoacridine derivative, but its pharmacokinetics and metabolism in body remain unknown. Using liquid chromatography tandem electrospray ionization mass spectrometry with the multiple reaction monitoring modes, we developed and validated a simple, rapid, sensitive and accurate technology for analyses of MBAA in the rat plasma, urine and bile. The micro samples were quickly prepared by 96-well plate.

Discovery of benzimidazole derivatives as novel multi-target EGFR, VEGFR-2 and PDGFR kinase inhibitors.

Multi-target EGFR, VEGFR-2 and PDGFR inhibitors are highly useful anticancer agents with improved therapeutic efficacies. In this work, we used two virtual screening methods, support vector machines (SVM) and molecular docking, to identify a novel series of benzimidazole derivatives, 2-aryl benzimidazole compounds, as multi-target EGFR, VEGFR-2 and PDGFR inhibitors. 2-Aryl benzimidazole compounds were synthesized and their biological activities against a tumor cell line HepG-2 and specific kinases were evaluated.

Exploration of acridine scaffold as a potentially interesting scaffold for discovering novel multi-target VEGFR-2 and Src kinase inhibitors.

VEGFR-2 and Src kinases both play important roles in cancers. In certain cancers, Src works synergistically with VEGFR-2 to promote its activation. Development of multi-target drugs against VEGFR-2 and Src is of therapeutic advantage against these cancers.

Novel synthetic 2-amino-10-(3,5-dimethoxy)benzyl-9(10H)-acridinone derivatives as potent DNA-binding antiproliferative agents.

A series of novel 9(10H)-acridinone derivatives with terminal amino substituents at C2 position on the acridinone ring were synthesized and studied for their antiproliferative activity and underlying mechanisms. These compounds demonstrated promising cytotoxicity to leukemia cells CCRF-CEM, displaying IC(50) values in the low micromolar range. Structure-activity relationships (SAR) indicated that the compound 6d bearing a pyrrolidine substituent and 8a with a methyl ammonium side chain displayed higher cytotoxicity to CCRF-CEM cells and also solid tumor cells A549, HepG2, and MCF7.