Discovery and SAR study of highly selective and potent 1,2,4-oxadiazole-based S1PR1 agonists.

Sphingosine-1-phosphate receptor 1 (S1PR1) is a validated therapeutic target for immune-mediated diseases such as multiple sclerosis and ulcerative colitis, owing to its critical role in regulating of lymphocyte migration. However, the clinical utility of current S1PR1 agonists is often limited by cardiovascular adverse effects, particularly dose-dependent bradycardia. Enhancing receptor subtype selectivity represents a promising strategy to mitigate these risks.

Direct Ser797 Interacted Pteridine-7(8)-one Derivatives as Highly Selective and Orally Available EGFR Inhibitors.

The EGFR mutation is the main mechanism of acquired resistance to Osimertinib in NSCLC. There is an urgent need for small-molecule inhibitors to overcome Osimertinib-resistance. In this article, we developed a series of pteridin-7(8)-one-derived inhibitors of EGFR (EGFR) integrating direct interactions with the mutated Ser797 residue and the hydrophobic pocket encircled by the gatekeeper Met790 residue.

Discovery of Tamsulosin Derivatives with Shifted Selectivity from the α-Adrenergic Receptor to ANO1 as Potent Antiosteoporotic Agents.

ANO1, a calcium-activated chloride channel, is a newly reported therapeutic target for osteoporosis. Tamsulosin (), an approved α-AR antagonist, was previously discovered to be a novel ANO1 allosteric inhibitor. Here, a series of derivatives were designed and synthesized with the aim of developing selective ANO1 inhibitors for osteoporosis treatment.

Design, Synthesis, and Biological Evaluation of Macrocyclic 2-Amino-4-phenylaminopyrimidine Derivatives as Potent JAK2 Inhibitors.

Janus kinase 2 with the activating mutation V617F is a potential target for the treatment of myeloproliferative neoplasms. Current JAK2 inhibitors often suffer from multiple pharmacological limitations such as limited selectivity and rapid metabolic clearance. In this study, we describe the design, synthesis, and biological evaluation of a series of macrocyclic 2-amino-4-phenylaminopyrimidine derivatives as JAK2 inhibitors.

Inactivation of RhoA for Hypertension Treatment Through the TRPV4-RhoA-RhoGDI1 Axis.

Background: The RhoA (Ras homolog family member A) signaling pathway is pivotal in regulating vascular smooth muscle cells (VSMCs) function and blood pressure homeostasis. Current inhibitors of the RhoA signaling pathway are limited in hypertension treatment, suffering from poor efficacy, insufficient specificity, and developmental challenges.

Methods: Cryo-electron microscopy (EM), proximity ligation assay (PLA), and site-directed mutagenesis were used to explore the mechanism of RhoA activity regulation.

Discovery of a Proteolysis-Targeting Chimera Degrader of JAK2 as a Potential Therapeutic Agent for JAK2-Mediated Myeloproliferative Neoplasms.

JAK2 is a promising target for treating myeloproliferative neoplasms (MPNs). However, existing JAK2 inhibitors cannot fully cure these diseases and may induce resistance with prolonged use. Here, we report the design, synthesis, and biological evaluation of a series of highly potent JAK2 degraders based on our previously developed inhibitor WWQ-131.

Structure-based design of novel pyrrolo[1,2-a]quinoxalin-4(5H)-one derivatives as potent noncovalent Bruton's tyrosine kinase (BTK) inhibitors.

Bruton's tyrosine kinase (BTK) is a promising target for the treatment of B cell malignancies. Developing noncovalent BTK inhibitors is a promising strategy to address the treatment limitations of covalent BTK inhibitors including off-target toxicity and acquired resistance. Our group previously discovered a novel noncovalent BTK inhibitor S2 with pyrrolo[1,2-α]quinoxalin-4(5H)-one as the scaffold.

Dual-Locking the SARS-CoV-2 Spike Trimer: An Amphipathic Molecular "Bolt" Stabilizes Conserved Druggable Interfaces for Coronavirus Inhibition.

The SARS-CoV-2 spike (S) protein, a trimeric structure comprising three receptor binding domains (RBDs) and three N-terminal domains (NTDs), undergoes substantial conformational changes to a fusion-prone open state for angiotensin-converting enzyme 2 (ACE2) binding and host cell infection. Stabilizing its closed state is a key antiviral strategy but remains challenging. Here, we introduce S416, a novel amphipathic molecule acting as a "molecular bolt".

Design, Synthesis, and Biological Evaluation of Pyrrolo[1,2-]quinoxalin-4(5)-one Derivatives as Potent and Orally Available Noncovalent Bruton's Tyrosine Kinase (BTK) Inhibitors.

Bruton's tyrosine kinase (BTK) is a therapeutic target for B-cell-driven malignancies. Most of the approved covalent BTK inhibitors are associated with treatment limitations due to off-target toxicity and drug resistance. Developing noncovalent BTK inhibitors is a promising strategy to address unmet clinical needs.

End-to-side anastomosis and autologous pulmonary artery patch for aortic coarctation and hypoplastic aortic arch.

Background: Aortic coarctation (CoA) is a congenital heart disease that usually combines various cardiovascular malformations, including hypoplastic aortic arch (HAA). We explore end-to-side anastomosis (ESA) and autologous pulmonary artery patch (APAP) in CoA with HAA, to provide more clinical experience.

Methods: This is a single-center retrospective study.

Tamsulosin ameliorates bone loss by inhibiting the release of Cl through wedging into an allosteric site of TMEM16A.

TMEM16A, a key calcium-activated chloride channel, is crucial for many physiological and pathological processes such as cancer, hypertension, and osteoporosis, etc. However, the regulatory mechanism of TMEM16A is poorly understood, limiting the discovery of effective modulators. Here, we unveil an allosteric gating mechanism by presenting a high-resolution cryo-EM structure of TMEM16A in complex with a channel inhibitor that we identified, Tamsulosin, which is resolved at 2.

Role of stimulated by retinoic acid 6 in 46 children of coarctation of the aorta.

(1) ObjectiveCoarctation of the aorta (CoA) is a complex congenital heart disease. Research on differential genes in patients with CoA and other groups of aortas and investigating the pathogenesis of aorta coarctation is essential for prevention and diagnosis. This study was conducted between January 2019 and December 2021.

Exploring drug-target interaction prediction on cold-start scenarios via meta-learning-based graph transformer.

Predicting drug-target interaction (DTI) is of great importance for drug discovery and development. With the rapid development of biological and chemical technologies, computational methods for DTI prediction are becoming a promising approach. However, there are few solutions to the cold-start problem in DTI prediction scenarios, as these methods rely on existing interaction information to support their modeling.

Design, synthesis, and biological evaluation of diphenyl ether substituted quinazolin-4-amine derivatives as potent EGFR inhibitors.

Epidermal growth factor receptor (EGFR) is a validated target for non-small-cell lung cancer (NSCLC). However, the treatment for EGFR-C797S mutation induced by third-generation EGFR inhibitors remains a concern. Therefore, the development of the fourth-generation EGFR inhibitors to overcome the EGFR-C797S mutation has great potential for clinical treatment.

Blocking the PD-1 signal transduction by occupying the phosphorylated ITSM recognition site of SHP-2.

Targeting the PD-1/PD-L1 axis with small-molecular inhibitors is a promising approach for immunotherapy. Here, we identify a natural pentacyclic triterpenoid, Pygenic Acid A (PA), as a PD-1 signaling inhibitor. PA exerts anti-tumor activity in hPD-1 knock-in C57BL/6 mice and enhances effector functions of T cells to promote immune responses by disrupting the PD-1 signaling transduction.

Design, synthesis and structure-activity relationship of malonic acid non-nucleoside derivatives as potent CD73 inhibitors.

High levels of extracellular adenosine in tumor microenvironment (TME) has extensive immunosuppressive effect. CD73 catalyzes the conversion of AMP into adenosine and regulates its production. Inhibiting CD73 can reduce the level of adenosine and reverse adenosine-mediated immune suppression.

Binding Free Energy Calculation Based on the Fragment Molecular Orbital Method and Its Application in Designing Novel SHP-2 Allosteric Inhibitors.

The accurate prediction of binding free energy is a major challenge in structure-based drug design. Quantum mechanics (QM)-based approaches show promising potential in predicting ligand-protein binding affinity by accurately describing the behavior and structure of electrons. However, traditional QM calculations face computational limitations, hindering their practical application in drug design.

Cross-view contrastive representation learning approach to predicting DTIs via integrating multi-source information.

Drug-target interaction (DTI) prediction serves as the foundation of new drug findings and drug repositioning. For drugs/targets, the sequence data contains the biological structural information, while the heterogeneous network contains the biochemical functional information. These two types of information describe different aspects of drugs and targets.

Targeting DHODH reveals therapeutic opportunities in ATRA-resistant acute promyelocytic leukemia.

Although all-trans retinoic acid (ATRA)-induced differentiation has transformed acute promyelocytic leukemia (APL) from the most fatal to the most curable hematological disease, resistance to ATRA in high-risk APL patients remains a clinical challenge. In this paper, we discovered that dihydroorotate dehydrogenase (DHODH) inhibition overcame ATRA resistance. 416, a potent DHODH inhibitor previously obtained in our group, inhibited the occurrence of APL in cells and model mice.

Macrocyclization of linear molecules by deep learning to facilitate macrocyclic drug candidates discovery.

Interest in macrocycles as potential therapeutic agents has increased rapidly. Macrocyclization of bioactive acyclic molecules provides a potential avenue to yield novel chemical scaffolds, which can contribute to the improvement of the biological activity and physicochemical properties of these molecules. In this study, we propose a computational macrocyclization method based on Transformer architecture (which we name Macformer).

Risk factors for recurrence after surgical repair of coarctation of the aorta in children: a single-center experience based on 51 children.

Background: Coarctation of the aorta (CoA), is a congenital malformation, often combined with several cardiac abnormalities. At present, the operation effect is satisfactory, but postoperative restenosis is still a matter. Identification of risk factors for restenosis and prompt therapy adjustments may improve patient outcomes.