Rational Optimization of Rho-Associated Coiled-Coil Containing Protein Kinase 2 Inhibitors via Disruption of Molecular Planarity for Pulmonary Fibrosis [0.03%]
通过破坏分子平面性合理优化Rho相关卷曲螺旋蛋白激酶2抑制剂以治疗肺纤维化
Zhi Cao,Shangfei Wei,Zhenhang Zhao et al.
Zhi Cao et al.
Given the therapeutic potential of ROCK2 in pulmonary fibrosis (PF) and the significant efficacy of our previously identified lead compound 1, we initiated an optimization campaign focused on addressing physicochemical liabilities through d...
Discovery of Potent and Orally Bioavailable Novel Cluster of Differentiation 38 (CD38) Small Molecule Inhibitors [0.03%]
一类新型高效的、口服生物利用度好的cluster of differentiation 38(CD38)小分子抑制剂的发现
Reza Shiroodi,Timothy J Montavon,Brandon M Nelson et al.
Reza Shiroodi et al.
Herein, we report the discovery and optimization of a series of cluster of differentiation 38 (CD38) inhibitors derived from a virtual ligand screening (VLS) campaign. VLS identified imidazopyridazine hit 9, which was optimized to a novel a...
Discovery and Optimization of 4-Methylquinazoline Derivatives as Highly Selective PI3Kδ Inhibitors for the Treatment of Acute Lung Injury [0.03%]
作为选择性PI3Kδ抑制剂用于治疗急性肺损伤的4-甲基喹唑啉衍生物的发现与优化
Deyu Wu,Mengyao Hao,Shuhan Dong et al.
Deyu Wu et al.
Phosphoinositide 3-kinase δ (PI3Kδ) has emerged as a promising therapeutic target for inflammatory respiratory diseases. Herein, we report the design and synthesis of a novel series of 4-methylquinazoline derivatives as potent and highly ...
Mitigating Excessive Mitochondrial Fission Through the Development of a Selective Macrocyclic Inhibitor Targeting Fis1/Mid51 Signaling [0.03%]
通过开发选择性巨环型抑制剂靶向Fis1 / Mid51信号来缓解过度线粒体分裂
Mulate Zerihun,Sayan Chakraborty,Ayetenew Abita et al.
Mulate Zerihun et al.
Mitochondrial fission protein 1 (Fis1) and mitochondrial dynamics protein of 51 kDa (Mid51) regulate stress-induced mitochondrial fragmentation implicated in cardiovascular disease. Using homologous sequence analysis and structure-guided de...
Discovery of FYJ-195 as a Highly Potent FLT3 Inhibitor against Multiple Acquired Resistance Mutations in Acute Myeloid Leukemia [0.03%]
FLT3抑制剂FYJ-195可有效克服急性髓系白血病的获得性耐药突变
Jin Yang,Ling-Yu Zhang,Xing-Feng Ni et al.
Jin Yang et al.
The efficacy of FLT3 inhibitors in acute myeloid leukemia (AML) is severely limited by resistance mutations, particularly the recalcitrant gatekeeper F691L and activation loop D835V/Y variants. Herein, through the structure-guided optimizat...
A Siderophore-Antibiotic Heterodimer Imaging Agent Enables In Vivo PET Imaging of S. aureus Infections [0.03%]
一种 siderophore-抗生素异二聚体成像剂实现了体内S. aureus感染的正电子发射断层扫描(PET)成像
Collin E Merrick,Mou Chakraborty,John M Van Wazer et al.
Collin E Merrick et al.
Only a handful of bacterial strains are responsible for the majority of clinical infections, with Staphylococcus aureus being the single largest contributor. S. aureus infections can be very hard to confirm and localize. There is a clinical...
Use of Human Dose Prediction Metrics to Enable Discovery of AZD3470, an MTA-Cooperative PRMT5 Inhibitor in Clinical Evaluation [0.03%]
用于预测人剂量的指标发现AZD3470并进入临床试验，一种与甲基转移酶共作的PRMT5抑制剂
James M Smith,Bernard Barlaam,David Beattie et al.
James M Smith et al.
Inhibition of the arginine methyltransferase protein arginine methyltransferase 5 (PRMT5) has emerged as a key target for cancer therapy. Leveraging the MTAP synthetic lethality mechanism, MTA-cooperative PRMT5 inhibitors are showing promis...
Dual Metabolic Blockade in Pancreatic Cancer: Potent Anticancer Activity of Mitochondria-Targeted Glycolysis and OXPHOS Inhibitors [0.03%]
双代谢抑制在胰腺癌中的应用：线粒体靶向糖酵解和OXPHOS抑制剂的抗癌活性研究
Haibo Yan,Dongsheng Li,Min Yang et al.
Haibo Yan et al.
Simultaneous targeting of glycolysis and oxidative phosphorylation (OXPHOS) is an effective strategy for overcoming the metabolic plasticity of pancreatic ductal adenocarcinoma (PDAC). In this study, we present compound 14c, a rationally de...
Targeting Multiple KRAS Mutations with High-Affinity Macrocyclic Inhibitors: From Discovery to Preclinical Validation [0.03%]
高亲和力环糊精KRAS多种突变抑制剂的研发与临床前验证
Dean P Phillips,Phil B Alper,Charles Y Cho et al.
Dean P Phillips et al.
The RAS Switch-II pockets' discovery enabled targeting a challenging molecular site. Covalent KRASG12C inhibitors inspired efforts to find compounds for other KRAS mutations, notably KRASG12D and KRASG12V. A macrocyclization strategy led to...
Kinetically Inert MRI/PET Probes with Myeloperoxidase-Triggered Covalent Capture for Quantitative Imaging of Acute Pancreatitis [0.03%]
用于急性胰腺炎定量成像的动态上惰性MRI / PET探针，具有髓过氧化物酶触发的共价捕获功能
Tiantian Luo,Lu Liu,Jie Yang et al.
Tiantian Luo et al.
Myeloperoxidase (MPO)-mediated oxidative stress drives inflammatory tissue injury, yet converting this enzyme activity into a selective and sustained imaging readout remains chemically challenging. To address this limitation, we report Mn-T...