Discovery of indoline-based derivatives as effective ROCK2 inhibitors for the potential new treatment of idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and devastating lung disease with a median survival of only 3-5 years. Due to the lack of effective therapy, IPF threatens human health. Recently, increasing reports have indicated that Rho-associated coiled-coil protein kinases (ROCKs) play important roles in the development of IPF and might represent a novel target for the treatment of IPF. Herein, a new series of selective ROCK2 inhibitors based on indoline were designed and synthesized. Structural modification resulted in optimized compound 9b with an IC50 value of 6 nM against ROCK2 and the inhibition of collagen gel contraction. Cellular assays demonstrated that 9b could significantly suppress the expression of collagen I and α-SMA, and inhibited ROCK signaling pathway. Oral administration of compound 9b (10 mg/kg) exerted more significant anti-pulmonary fibrosis effects than nintedanib (100 mg/kg) and KD025 (100 mg/kg) in a bleomycin-induced IPF rat model, suggesting that 9b could serve as a potential lead compound for the treatment of IPF.

Synthesis and biological evaluation of 6-(pyrimidin-4-yl)-1H-pyrazolo[4,3-b]pyridine derivatives as novel dual FLT3/CDK4 inhibitors.

FMS-like tyrosine kinase-3 (FLT3) and cyclin-dependent kinase 4/6 (CDK4/6) inhibitors have been proven to play a significant role in tumor therapy. Herein, based on the previously reported JAK2/FLT3 inhibitor 18e, we described the synthesis, structure-activity relationship and biological evaluation of a series of unique 6-(pyrimidin-4-yl)-1H-pyrazolo[4,3-b]pyridine derivatives that inhibited FLT3 and CDK4 kinases. The optimized compound 23k exhibited low nanomolar range activities with IC50 values of 11 and 7 nM for FLT3 and CDK4, respectively. In the MV4-11 xenograft tumor model, the tumor growth inhibition rate of 23k dosed at 200 mg/kg was 67%, suggesting that 23k possessed an antitumor therapeutic effect.

Identification of in vivo metabolites of a potential anti-rheumatoid arthritis compound, the quinazolinone derivative PD110, using ultra-high performance liquid chromatography coupled with Q-Exactive plus mass spectrometrys.

The objective of this study was to identify metabolites of PD110 by UHPLC-Q-Exactive Plus MS and determine its metabolic pathways in vivo.Mouse urine, faeces, and plasma samples were collected after an intraperitoneal administration of PD110 at a single dose of 30 mg·kg-1.The metabolites were detected and identified by UHPLC-Q-Exactive Plus MS and Compound DiscovererTM 2.0 software.In total, 44 metabolites (including 31 phase-I and 13 phase-II metabolites) were preliminarily identified according to the mass accuracy (<5 ppm) and comparison of their mass spectrometry profiles. Oxidation, glucuronide conjugation, and glucoside conjugation were the main metabolic pathways of PD110 in mice.This research first focussed on the biotransformation of PD110 in mice, and its metabolites may provide pivotal information for further pharmacological and clinical studies.

Metabolic profiling in liver microsomes and mice of E28, a potent FLT3 inhibitor.

The objective of this study was to clarify the species differences of metabolic stability of E28 in liver microsomes, and to study metabolic phenotypes of E28 in human liver microsomes by chemical inhibition method.The metabolites in plasma, urine, and faeces samples from mice received caudal vein intravenous were detected and identified by UHPLC-HRMS, and the tissue distribution was studied after oral administration.E28 was metabolised rapidly in liver microsomes of each species with a short half-live T1/2 and a moderate clearance, except for rats. The metabolic properties of E28 were similar in human and mouse liver microsomes. Data from metabolic phenotype studies indicated that CYP2D6, CYP3A4 and CYP2C9 were the main metabolic enzymes participating in the metabolism of E28.The main metabolic pathways implicated include oxidation, methylation, amide hydrolysis, acetylation, glucuronide conjugation.Tissue distribution studies showed that E28 could be detected in all organs and tissues after oral administration, with the highest level in the stomach and the lowest in the brain. In bone marrow cells, the concentration of E28 in all sample points were consistently higher than its half inhibitory concentration against MV4-11 tumour cells.

Insights into spinal muscular atrophy from molecular biomarkers.

ABSTRACT: Spinal muscular atrophy is a devastating motor neuron disease characterized by severe cases of fatal muscle weakness. It is one of the most common genetic causes of mortality among infants aged less than 2 years. Biomarker research is currently receiving more attention, and new candidate biomarkers are constantly being discovered. This review initially discusses the evaluation methods commonly used in clinical practice while briefly outlining their respective pros and cons. We also describe recent advancements in research and the clinical significance of molecular biomarkers for spinal muscular atrophy, which are classified as either specific or non-specific biomarkers. This review provides new insights into the pathogenesis of spinal muscular atrophy, the mechanism of biomarkers in response to drug-modified therapies, the selection of biomarker candidates, and would promote the development of future research. Furthermore, the successful utilization of biomarkers may facilitate the implementation of gene-targeting treatments for patients with spinal muscular atrophy.

Podocyte injury of diabetic nephropathy: Novel mechanism discovery and therapeutic prospects.

Diabetic nephropathy (DN) is a severe complication of diabetes mellitus, posing significant challenges in terms of early prevention, clinical diagnosis, and treatment. Consequently, it has emerged as a major contributor to end-stage renal disease. The glomerular filtration barrier, composed of podocytes, endothelial cells, and the glomerular basement membrane, plays a vital role in maintaining renal function. Disruptions in podocyte function, including hypertrophy, shedding, reduced density, and apoptosis, can impair the integrity of the glomerular filtration barrier, resulting in elevated proteinuria, abnormal glomerular filtration rate, and increased creatinine levels. Hence, recent research has increasingly focused on the role of podocyte injury in DN, with a growing emphasis on exploring therapeutic interventions targeting podocyte injury. Studies have revealed that factors such as lipotoxicity, hemodynamic abnormalities, oxidative stress, mitochondrial dysfunction, and impaired autophagy can contribute to podocyte injury. This review aims to summarize the underlying mechanisms of podocyte injury in DN and provide an overview of the current research status regarding experimental drugs targeting podocyte injury in DN. The findings presented herein may offer potential therapeutic targets and strategies for the management of DN associated with podocyte injury.

Identification of abemaciclib derivatives targeting cyclin-dependent kinase 4 and 6 using molecular dynamics, binding free energy calculation, synthesis, and pharmacological evaluation.

CDK4/6 plays a crucial role in various cancers and is an effective anticancer drug target. However, the gap between clinical requirements and approved CDK4/6 drugs is unresolved. Thus, there is an urgent need to develop selective and oral CDK4/6 inhibitors, particularly for monotherapy. Here, we studied the interaction between abemaciclib and human CDK6 using molecular dynamics simulations, binding free energy calculations, and energy decomposition. V101 and H100 formed stable hydrogen bonds with the amine-pyrimidine group, and K43 interacted with the imidazole ring via an unstable hydrogen bond. Meanwhile, I19, V27, A41, and L152 interacted with abemaciclib through π-alkyl interactions. Based on the binding model, abemaciclib was divided into four regions. With one region modification, 43 compounds were designed and evaluated using molecular docking. From each region, three favorable groups were selected and combined with each other to obtain 81 compounds. Among them, C2231-A, which was obtained by removing the methylene group from C2231, showed better inhibition than C2231. Kinase profiling revealed that C2231-A showed inhibitory activity similar to that of abemaciclib; additionally, C2231-A inhibited the growth of MDA-MB-231 cells to a greater extent than did abemaciclib. Based on molecular dynamics simulation, C2231-A was identified as a promising candidate compound with considerable inhibitory effects on human breast cancer cell lines.

Discovery, Optimization, and Evaluation of Potent and Selective PI3Kδ-γ Dual Inhibitors for the Treatment of B-cell Malignancies.

Nowadays, PI3Kδ-γ dual inhibitors have been approved for the treatment of B-cell malignancies. Dual inhibition of PI3Kδ and PI3Kγ represents a unique therapeutic opportunity and may confer greater benefits than either isoform inhibition alone in the management of hematological malignancies. However, currently available dual inhibitors of PI3Kδ-γ compromise in at least one of several essential properties in terms of potency, selectivity, and pharmacokinetic (PK) profiles. Hence, the main challenge of our optimization campaign was to identify an oral available PI3Kδ-γ dual inhibitor with an optimum balance of potency, selectivity, and PK profiles. The medicinal chemistry efforts culminated in the discovery of compound 58, which exhibited strong potency and high selectivity along with excellent in vivo profiles as demonstrated through PK studies in rats and through pharmacodynamic studies in an SUDHL-6 xenograft model. All the results suggest that compound 58 may be a promising candidate for the treatment of B-cell malignancies.

[Clinical analysis and literature review of primary melanoma in nasal cavity and sinus--report of 9 cases].

OBJECTIVE: To analyze and summarize clinical characteristic, treatment scheme and survival rate of primary melanom in nasal cavity and sinus. METHOD: We retrospectively analyzed the 9 patients with primary melanom in nasal cavity and sinus who in data proceed were treated and reviewed the related literature. RESULT: Among the 9 patients, the clinical main symptoms are rhinostegnosis of lateral nasal and intermittent nasal bleeding. Pathologic examination is mainly characterized by tumor cells abnormity and cytoplasm containing pigment or without pigment, and main diagnosis basis is some or all of the positive for HMB45, S-100, melan-A. The survival rate are 88.9% (8/9) of 1-year, 66.7% (6/9) of 3-year and 33.3% (3/9) of 5-year. CONCLUSION: The incidence of primary melanom in nasal cavity and sinusis is not frequent in clinic and confirmed by immunohistochemical. The extensive radical excision of focus and combine adjuvant radiotherapy postoperative may improve the survival rate of patients.