Optimization of a series of novel, potent and selective Macrocyclic SYK inhibitors.

Spleen tyrosine kinase (SYK) is a non-receptor cytoplasmic kinase. Due to its pivotal role in B cell receptor and Fc-receptor signalling, inhibition of SYK has been a target of interest in a variety of diseases. Herein, we report the use of structure-based drug design to discover a series of potent macrocyclic inhibitors of SYK, with excellent kinome selectivity and in vitro metabolic stability. We were able to remove hERG inhibition through the optimization of physical properties, and utilized a pro-drug strategy to address permeability challenges.

Comparison of Improved Surgical Eight-Step Handwashing Combined with ATP Fluorescence in Detecting the Infection Rate at the Site of Seven-Step Surgical Handwashing and 30-Day Orthopaedic Surgery: A Randomized Study.

Objectives: To compare the effects of two hand cleaning schemes on the prevention of surgical site infection in routine orthopaedic surgery. Compared with the standard surgical seven-step washing technique and detected by ATP fluorescence method, the handwashing effects of the improved surgical eight-step washing technique and the standard surgical seven-step washing technique were compared, so as to provide a basis for eliminating the handwashing blind area of the surgical seven step washing technique and improving the surgical handwashing method. Methods: A total of 800 consecutive patients who underwent clean and clean-contaminated orthopaedic surgery between January 1, 2020 and December 31, 2020. Twenty orthopaedic doctors in the operating room of our research team were randomly divided into the improved eight-step washing technique group (improved group) and the traditional seven-step washing technique group (traditional group), with 10 people in each group. Each person was randomly sampled 40 times, 400 people in each group, a total of 800 people, and completed by stages in 12 months. Main Outcome Measures. The infection rate of surgical site 30 days after operation was the primary end point. The qualified rate of fingertip culture was combined with ATP fluorescence in the two groups and three new culture areas in the two groups: the lateral edge of the palm, the medial edge of the palm, and the nail groove of the middle finger and the nail root were secondary end points. Results: The 2 protocols were comparable in regard to surgical site infection risk factors. The infection rate of surgical site in the traditional group was 10 cases (2.50%) in 400 cases and 0 cases (0%) in the improved group. Three culture areas were added: the qualified rate of lateral edge of palm, medial edge of palm, and nail groove and nail root of middle finger, and the nosocomial infection rate of surgical incision between the two groups was statistically significant (P < 0.05). There was no significant difference in the qualified rate of fingertip culture (P > 0.05). The handwashing scheme in this study meets the recommended duration of hand disinfection and has good tolerance, and the skin dryness and skin irritation after using aqueous solution are similar. Conclusions: The improved surgical eight-step washing technique combined with ATP fluorescence detection is helpful to eliminate the "blind area" of handwashing. It is also necessary to add three training areas. Handwashing and training are more scientific, rigorous, and effective. They are effective in reducing orthopaedic surgical infection and have application value. They can safely replace the traditional surgical seven-step washing technique, which is worthy of clinical promotion.

Discovery of a Potent and Selective ATAD2 Bromodomain Inhibitor with Antiproliferative Activity in Breast Cancer Models.

ATAD2 is an epigenetic bromodomain-containing target which is overexpressed in many cancers and has been suggested as a potential oncology target. While several small molecule inhibitors have been described in the literature, their cellular activity has proved to be underwhelming. In this work, we describe the identification of a novel series of ATAD2 inhibitors by high throughput screening, confirmation of the bromodomain region as the site of action, and the optimization campaign undertaken to improve the potency, selectivity, and permeability of the initial hit. The result is compound 5 (AZ13824374), a highly potent and selective ATAD2 inhibitor which shows cellular target engagement and antiproliferative activity in a range of breast cancer models.

Optimization of an Imidazo[1,2-a]pyridine Series to Afford Highly Selective Type I1/2 Dual Mer/Axl Kinase Inhibitors with In Vivo Efficacy.

Inhibition of Mer and Axl kinases has been implicated as a potential way to improve the efficacy of current immuno-oncology therapeutics by restoring the innate immune response in the tumor microenvironment. Highly selective dual Mer/Axl kinase inhibitors are required to validate this hypothesis. Starting from hits from a DNA-encoded library screen, we optimized an imidazo[1,2-a]pyridine series using structure-based compound design to improve potency and reduce lipophilicity, resulting in a highly selective in vivo probe compound 32. We demonstrated dose-dependent in vivo efficacy and target engagement in Mer- and Axl-dependent efficacy models using two structurally differentiated and selective dual Mer/Axl inhibitors. Additionally, in vivo efficacy was observed in a preclinical MC38 immuno-oncology model in combination with anti-PD1 antibodies and ionizing radiation.

Survivin and vascular endothelial growth factor are associated with spontaneous pulmonary metastasis of osteosarcoma: Development of an orthotopic mouse model.

The high rate of pulmonary metastases of osteosarcoma (OS) presents a therapeutic challenge in the field of orthopedics. Therefore, there is a marked requirement to establish a spontaneous pulmonary metastasis animal model of OS, within which potential antitumor agents may be evaluated for their ability to inhibit the growth and pulmonary metastasis of OS, as well as to identify potentially associated biomarkers of OS metastasis. In the present study, rodent OS cells (UMR106-01) were injected into the right tibia of athymic nude mice. The mice were sacrificed weekly by cervical dislocation at one to five weeks following inoculation. The orthotopic mice developed tumor masses in the right tibia one week following inoculation. At three weeks, multiple nodules were observed in the lungs. The expression of survivin and vascular endothelial growth factor (VEGF) was analyzed in the tumors and lungs via immunohistochemistry. The positive expression of survivin and VEGF was identified in the local tumor and lung tissue of the orthotopic mice, however was not observed in the tissues of the healthy control mice. The orthotopic model established in the current study presents a valuable tool for the investigation of factors that promote or inhibit OS growth and/or metastasis. In addition, it was identified that survivin and VEGF may be significant in the lung metastasis of OS.