Design, synthesis, and biological studies of nitric oxide-donating piperlongumine derivatives triggered by lysyl oxidase as anti-triple negative breast cancer agents.

Nitric oxide (NO) is an important gas messenger molecule with a wide range of biological functions. High concentration of NO exerts promising antitumor effects and is regarded as one of the hot spots in cancer research, that have limitations in their direct application due to its gaseous state, short half-life (seconds) and high reactivity. Lysyl oxidase (LOX) is a copper-dependent amine oxidase that is responsible for the covalent bonding between collagen and elastin and promotes tumor cell invasion and metastasis. The overexpression of LOX in triple-negative breast cancer (TNBC) makes it an attractive target for TNBC therapy. Herein, novel NO donor prodrug molecules were designed and synthesized based on the naturally derived piperlongumine (PL) skeleton, which can be selectively activated by LOX to release high concentrations of NO and PL derivatives, both of them play a synergistic role in TNBC therapy. Among them, the compound TM-1 selectively released NO in highly invasive TNBC cells (MDA-MB-231), and TM-1 was also confirmed as a potential TNBC cell line inhibitor with an inhibitory concentration of 2.274 µM. Molecular docking results showed that TM-1 had a strong and selective binding affinity with LOX protein.

The Denoising Method for Transformer Partial Discharge Based on the Whale VMD Algorithm Combined with Adaptive Filtering and Wavelet Thresholding.

Partial discharge (PD) is the primary factor causing insulation degradation in transformers. However, the collected signals of partial discharge are often contaminated with significant noise. This makes it difficult to extract the PD signal and hinders subsequent signal analysis and processing. This paper proposes a denoising method for transformer partial discharge based on the Whale VMD algorithm combined with adaptive filtering and wavelet thresholding (WVNW). First, the WOA is used to optimize the important parameters of the VMD. The selected mode components from the VMD decomposition are then subjected to preliminary denoising based on the kurtosis criterion. The reconstructed signal is further denoised using the Adaptive Filter (NLMS) algorithm to remove narrowband interference noise. Finally, the residual white noise is eliminated using the Wavelet Thresholding algorithm. In simulation experiments and practical measurements, the proposed method is compared quantitatively with previous methods, VMD-WT, and EMD-WT, based on metrics such as SNR, RMSE, NCC, and NRR. The results indicate that the WVNW method effectively suppresses noise interference and restores the original PD signal waveform with high waveform similarity while preserving a significant amount of local discharge signal features.

Discovery of a novel ALK/ROS1/FAK inhibitor, APG-2449, in preclinical non-small cell lung cancer and ovarian cancer models.

BACKGROUND: Tyrosine kinase inhibitors (TKIs) are mainstays of cancer treatment. However, their clinical benefits are often constrained by acquired resistance. To overcome such outcomes, we have rationally engineered APG-2449 as a novel multikinase inhibitor that is highly potent against oncogenic alterations of anaplastic lymphoma kinase (ALK), ROS proto-oncogene 1 receptor tyrosine kinase (ROS1), and focal adhesion kinase (FAK). Here we present the preclinical evaluation of APG-2449, which exhibits antiproliferative activity in cells carrying ALK fusion or secondary mutations. METHODS: KINOMEscan® and LANCE TR-FRET were used to characterize targets and selectivity of APG-2449. Water-soluble tetrazolium salt (WST-8) viability assay and xenograft tumorigenicity were employed to evaluate therapeutic efficacy of monotherapy or drug combination in preclinical models of solid tumors. Western blot, pharmacokinetic, and flow cytometry analyses, as well as RNA sequencing were used to explore pharmacokinetic-pharmacodynamic correlations and the mechanism of actions driving drug combination synergy. RESULTS: In mice bearing wild-type or ALK/ROS1-mutant non-small-cell lung cancer (NSCLC), APG-2449 demonstrates potent antitumor activity, with correlations between pharmacokinetics and pharmacodynamics in vivo. Through FAK inhibition, APG-2449 sensitizes ovarian xenograft tumors to paclitaxel by reducing CD44+ and aldehyde dehydrogenase 1-positive (ALDH1+) cancer stem cell populations, including ovarian tumors insensitive to carboplatin. In epidermal growth factor receptor (EGFR)-mutated NSCLC xenograft models, APG-2449 enhances EGFR TKI-induced tumor growth inhibition, while the ternary combination of APG-2449 with EGFR (osimertinib) and mitogen-activated extracellular signal-regulated kinase (MEK; trametinib) inhibitors overcomes osimertinib resistance. Mechanistically, phosphorylation of ALK, ROS1, and FAK, as well as their downstream components, is effectively inhibited by APG-2449. CONCLUSIONS: Taken together, our studies demonstrate that APG-2449 exerts potent and durable antitumor activity in human NSCLC and ovarian tumor models when administered alone or in combination with other therapies. A phase 1 clinical trial has been initiated to evaluate the safety and preliminary efficacy of APG-2449 in patients with advanced solid tumors, including ALK+ NSCLC refractory to earlier-generation ALK inhibitors. TRIAL REGISTRATION: Clinicaltrial.gov registration: NCT03917043 (date of first registration, 16/04/2019) and Chinese clinical trial registration: CTR20190468 (date of first registration, 09/04/2019).

Anatomy and Correlation of the Coracoid Process and Coracoclavicular Ligament Based on Three-Dimensional Computed Tomography Reconstruction and Magnetic Resonance Imaging.

BACKGROUND The anatomy of the coracoid process and coracoclavicular (CC) ligament have been described and the correlation between them has been assessed based on 3-dimensional computed tomography (CT) reconstruction and magnetic resonance imaging (MRI), which provide a guide for coracoclavicular ligament reconstruction. MATERIAL AND METHODS Data were collected from 300 patients who underwent both CT and MRI of the shoulder joint from January 2017 to January 2019 at the Jiang'an Hospital of Traditional Chinese Medicine. The coracoid process was observed and classified and parameters of the CC ligament were measured according to different corneal types. All of the statistics were collected and classified by 2 radiologists, and average values were determined.Measurements of segments were taken as follows: ab - In the coronal plane, the length of the CC ligament from the central point of the CC ligament at the clavicular attachment to the CC ligament at the center of the CC attachment); ac - The distance from the center point of the CC ligament at the supraclavicular attachment to the acromioclavicular joint; de - In the sagittal plane, the length of the CC ligament from the center of the clavicular attachment to the coracoid attachment point; fg - The maximum diameter of the CC ligament at the anterior and posterior margins of the clavicle attachment; hi - The largest diameter of the CC ligament at the anterior and posterior edge of the coracoid process attachment; dj - The distance of the coracoclavicular ligament from the center point of the coracoid process attachment to the coracoid process tip; kl - The distance in the supraclavicular plane from the coracoclavicular ligament to the subcoracoid process. RESULTS The analysis showed that there are 5 types of coracoid process: gourd (31%), short rod (20%), long rod (22.3%), wedge (10.3%), and water drop (6.3%). There were statistically significant differences between the lengths of the ac and hi segments in the among the wedge and gourd-type and the short rod and water drop-type coracoid processes. There were statistically significant differences between the lengths of the ab, de, and fg segments in the short rod, gourd, and long rod-type coracoid processes. There were statistically significant differences between the lengths of the ac, fg, hi, dj, and kl segments in the water drop, gourd, and long rod-type coracoid processes. CONCLUSIONS The present study indicated that measurement of the CC ligament and the different shapes of the coracoid process provide an anatomical basis for the diagnosis and treatment of shoulder diseases and the data can be used to improve the safety of CC ligament reconstruction.

Preclinical development of HQP1351, a multikinase inhibitor targeting a broad spectrum of mutant KIT kinases, for the treatment of imatinib-resistant gastrointestinal stromal tumors.

BACKGROUND: Imatinib shows limited efficacy in patients with gastrointestinal stromal tumors (GISTs) carrying secondary KIT mutations. HQP1351, an orally bioavailable multikinase BCR-ABL inhibitor, is currently in clinical trials for the treatment of T315I mutant chronic myelogenous leukemia (CML), but the potential application in imatinib-resistant GISTs carrying secondary KIT mutations has not been explored. METHODS: The binding activities of HQP1351 with native or mutant KIT were first analyzed. Imatinib-sensitive GIST T1 and imatinib-resistant GIST 430 cells were employed to test the in vitro antiproliferative activity. Colony formation assay, cell migration assay and cell invasion assay were performed to evaluate the clonogenic, migration and invasion ability respectively. Flow cytometry and western blot analysis were used to detect cell apoptosis, cell cycle and signaling pathway. In vivo antitumor activity was evaluated in mouse xenograft models derived from GIST cell lines. RESULTS: HQP1351 potently inhibited both wild-type and mutant KIT kinases. In both imatinib-resistant and sensitive GIST cell lines, HQP1351 exhibited more potent or equivalent antiproliferative activity compared with ponatinib, a third generation BCR-ABL and KIT inhibitor. HQP1351 led to more profound inhibition of cell colony formation, cell migration and invasion, cell cycle arrest and cell apoptosis than ponatinib. Furthermore, HQP1351 also inhibited p-KIT, p-AKT, p-ERK1/2, and p-STAT3 to a higher extent than ponatinib. Finally, in xenograft tumor models derived from imatinib-resistant GIST cancer cell lines, HQP1351 exhibited antitumor activity superior to ponatinib. CONCLUSIONS: Collectively, our in vitro and in vivo results suggest that the therapeutic application of HQP1351 in imatinib-resistant GIST patients deserves further investigation in clinical trials.