Reprogramming macrophage polarization with a small molecule G3I: Enhancing tumor suppression and inflammation control.

Glycogen synthase kinase-3β (GSK-3β) is a ubiquitously expressed serine/threonine kinase that plays a pivotal role in regulating innate and adaptive immunity by modulating the production of pro- and anti-inflammatory cytokines. To investigate specific regulators of GSK-3β in innate immunity, we developed small molecule inhibitors that are tightly interact with three ATP-binding sites of GSK-3β through a systematic Fragment-based de novo design (FBDND). Among the leading candidates, G3I was found to modulate early macrophage polarization by downregulating the expression of mRNAs of M2-like markers such as CD206, Arg-1, CCL18 and upregulating the markers for M1-like macrophages such as CD86 and CCR7.

Synergistic optimizations of efficacy and membrane permeability of IRAK4 inhibitors: identifying new lead compounds for anti-inflammatory therapeutics.

Interleukin-1 receptor-associated kinase 4 (IRAK4) is a serine/threonine kinase that plays a pivotal role in immune signalling and cytokine regulation, making it a compelling target for the treatment of inflammatory and autoimmune diseases. We initiated a drug discovery campaign based on the -diphenylpyrimidine-2,4-diamine (DPDA) scaffold, employing an integrated strategy that combined structure-based design, three-dimensional quantitative structure-activity relationship (3D-QSAR) modelling, and biochemical evaluation. This approach emphasised the optimisation of membrane permeability by controlling the 1-octanol/water partition coefficient (Log), while also enforcing configurational constraints to enhance IRAK4-specific binding.

Concurrent Optimizations of Efficacy and Blood-Brain Barrier Permeability in New Macrocyclic LRRK2 Inhibitors for Potential Parkinson's Disease Therapeutics.

The elevated activity of leucine-rich repeat kinase 2 (LRRK2) is implicated in the pathogenesis of Parkinson's disease (PD). The quest for effective LRRK2 inhibitors has been impeded by the formidable challenge of crossing the blood-brain barrier (BBB). We leveraged structure-based de novo design and developed robust three-dimensional quantitative structure-activity relationship (3D-QSAR) models to predict BBB permeability, enhancing the likelihood of the inhibitor's brain accessibility.

Nucleophilic C4-selective (hetero) arylation of pyridines for facile synthesis of heterobiaryls.

The synthesis of heterobiaryl compounds holds significant value in organic chemistry due to their extensive range of applications. Herein, we report a highly efficient strategy for conducting C4-selective (hetero) arylation of pyridines using -aminopyridinium salts. The reaction proceeds readily at room temperature in the presence of a base, thus eliminating the requirement for catalysts or oxidants.

Structure-Based Virtual Screening and De Novo Design to Identify Submicromolar Inhibitors of G2019S Mutant of Leucine-Rich Repeat Kinase 2.

Missense mutations of leucine-rich repeat kinase 2 (LRRK2), including the G2019S mutant, are responsible for the pathogenesis of Parkinson's disease. In this work, structure-based virtual screening of a large chemical library was carried out to identify a number of novel inhibitors of the G2019S mutant of LRRK2, the biochemical potencies of which ranged from the low micromolar to the submicromolar level. The discovery of these potent inhibitors was made possible due to the modification of the original protein-ligand binding energy function in order to include an accurate ligand dehydration energy term.

A novel DDR1 inhibitor enhances the anticancer activity of gemcitabine in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is an extracellular matrix (ECM)-rich carcinoma, which promotes chemoresistance by inhibiting drug diffusion into the tumor. Discoidin domain receptor 1 (DDR1) increases tumor progression and drug resistance by binding to collagen, a major component of tumor ECM. Therefore, DDR1 inhibition may be helpful in cancer therapeutics by increasing drug delivery efficiency and improving drug sensitivity.

Two-Track Virtual Screening Approach to Identify the Dual Inhibitors of Wild Type and C481S Mutant of Bruton's Tyrosine Kinase.

Bruton's tyrosine kinase (BTK) is responsible for the pathogenesis of various autoimmune diseases and chronic lymphocytic leukemia. However, the discovery of efficient medicines has seen limited success due to the constitutively active mutants that acquired the drug resistance. To disclose the dual inhibitors against the wild-type BTK and the problematic drug-resistant C481S mutant, a large chemical library was virtually screened with extensive molecular docking simulations using two target proteins.

Discovery of a novel NUAK1 inhibitor against pancreatic cancer.

The novel (nua) kinase family 1 (NUAK1) is an AMPK-related kinase and its expression is associated with tumor malignancy and poor prognosis in several types of cancer, suggesting its potential as a target for cancer therapy. Therefore, the development of NUAK1-targeting inhibitors could improve therapeutic outcomes in cancer. We synthesized KI-301670, a novel NUAK1 inhibitor, and assessed its anticancer effects and mechanism of action in pancreatic cancer.

Structure-Based Virtual Screening and De Novo Design of PIM1 Inhibitors with Anticancer Activity from Natural Products.

Background: the proviral insertion site of Moloney murine leukemia (PIM) 1 kinase has served as a therapeutic target for various human cancers due to the enhancement of cell proliferation and the inhibition of apoptosis.

Methods: to identify effective PIM1 kinase inhibitors, structure-based virtual screening of natural products of plant origin and de novo design were carried out using the protein-ligand binding free energy function improved by introducing an adequate dehydration energy term.

Results: as a consequence of subsequent enzyme inhibition assays, four classes of PIM1 kinase inhibitors were discovered, with the biochemical potency ranging from low-micromolar to sub-micromolar levels.

Rational Computational Design of Fourth-Generation EGFR Inhibitors to Combat Drug-Resistant Non-Small Cell Lung Cancer.

Although the inhibitors of singly mutated epidermal growth factor receptor (EGFR) kinase are effective for the treatment of non-small cell lung cancer (NSCLC), their clinical efficacy has been limited due to the emergence of various double and triple EGFR mutants with drug resistance. It has thus become urgent to identify potent and selective inhibitors of triple mutant EGFRs resistant to first-, second-, and third-generation EGFR inhibitors. Herein, we report the discovery of potent and highly selective inhibitors of EGFR exon 19 p.

Kinase and GPCR polypharmacological approach for the identification of efficient anticancer medicines.

Discovery of an anticancer medicine using a single target protein has often been unsuccessful due to the complexity of pathogenic mechanisms as well as the presence of redundant signaling pathways. In this work, we attempted to find promising anticancer drug candidates by simultaneously targeting casein kinase 1 delta (CK1δ) and muscarinic acetylcholine receptor M3 (M3R). Through the structure-based virtual screening and de novo design with the modified potential function for protein-ligand binding, a series of benzo[4,5]imidazo[1,2-a][1,3,5]triazine-2-amine (BITA) derivatives were identified as CK1δ inhibitors and also as M3R antagonists.