Discovery of the salicylaldehyde-based compound DDO-02267 as a lysine-targeting covalent inhibitor of ALKBH5.

N-methyladenosine (mA) is a crucial mRNA epigenetic modification in eukaryotes, and its methylation regulation is associated with the proliferation and metastasis of diverse tumor cells. ALKBH5 functions as a demethylase for mA and plays a role in the demethylation process, thus influencing tumor cell growth and migration. However, there are limited reports on selective small molecule inhibitors of ALKBH5.

Discovery and Development of NLRP3 Inhibitors Targeting the LRR Domain to Disrupt NLRP3-NEK7 Interaction for the Treatment of Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a chronic autoimmune disease. Targeting NLRP3 inflammasome, specifically its interaction with NEK7 via the LRR domain of NLRP3, is a promising therapeutic strategy. Our research aimed to disrupt this interaction by focusing on the LRR domain.

Discovery of Pyrazolo[1,5-]pyrimidine Derivative as a Novel and Selective ALKBH5 Inhibitor for the Treatment of AML.

MA (-methyladenosine) plays a significant role in regulating RNA processing, splicing, nucleation, translation, and stability. AlkB homologue 5 (ALKBH5) is an Fe(II)/2-oxoglutarate (2-OG)-dependent dioxygenase that demethylates mono- or dimethylated adenosines. ALKBH5 can be regarded as an oncogenic factor for various human cancers.

Inhibitors of Stimulator of Interferon Genes from 2019 to July 2022: An Overview of the Structure and Bioactivity.

Stimulator of interferon genes (STING) plays a vital role in the human innate immune system. Aberrant expression of STING has been proven to be associated with several diseases, such as STING-associated vasculopathy with onset in infancy, Aicardi-Goutieres syndrome, and systemic lupus erythematosus. Therefore, inhibition of the STING signaling pathway can also be expected to provide effective therapeutic strategies for treating specific inflammatory and autoimmune diseases.

Development of Orally Bioavailable Amidobenzimidazole Analogues Targeting Stimulator of Interferon Gene (STING) Receptor.

Stimulator of interferon gene (STING) is a critical adaptor protein that has a pivotal role in triggering inherent immune responses to infection. STING-linked interferon production has been involved in anti-inflammation, anti-infection, and antitumor immunity. Herein, a series of amidobenzimidazole analogues as STING agonists were profiled for potency and drug-like properties.

Medicinal chemistry perspective on cGAS-STING signaling pathway with small molecule inhibitors.

The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway serves as a pivotal mediator of innate immunity by triggering the secretion of type I interferons and other proinflammatory cytokines. In view of the immune-related diseases caused by abnormal activity of the cGAS-STING signaling pathway, considerable progress in this field has encouraged the discovery of cGAS-STING inhibitors in the past five years. In this review, we will focus on the link between the cGAS-STING signaling pathway and autoimmune and inflammatory disorders, summarize the development and optimization of cGAS-STING signaling pathway inhibitors, discuss the therapeutic effects on inflammatory diseases and propose suggestions and insights for future exploitation.

Hematopoietic Progenitor Kinase 1 in Tumor Immunology: A Medicinal Chemistry Perspective.

Hematopoietic progenitor kinase 1 (HPK1), a hematopoietic cell-restricted member of the serine/threonine Ste20-related protein kinases, is a negative regulator of the T cell receptor, B cell receptor, and dendritic cells. Loss of HPK1 kinase function increases cytokine secretion and enhances T cell signaling, virus clearance, and tumor growth inhibition. Therefore, HPK1 is considered a promising target for tumor immunotherapy.

Discovery of 2-((2-methylbenzyl)thio)-6-oxo-4-(3,4,5-trimethoxyphenyl)-1,6-dihydropyrimidine-5-carbonitrile as a novel and effective bromodomain and extra-terminal (BET) inhibitor for the treatment of sepsis.

Sepsis has long been a major health problem worldwide. It threatens the lives of hospitalized patients and has been one of the leading causes of death in hospitalized patients over the past decades. BRD4 has been regarded as a potential target for sepsis therapy, for its critical role in the transcriptional expression of NF-κB pathway-dependent inflammatory factors.

Target Fishing Reveals a Novel Mechanism of 1,2,4-Oxadiazole Derivatives Targeting Rpn6, a Subunit of 26S Proteasome.

1,2,4-Oxadiazole derivatives, a class of Nrf2-ARE activators, exert an extensive therapeutic effect on inflammation, cancer, neurodegeneration, and microbial infection. Among these analogues, is the most potent Nrf2 activator and used as the core structure for bioactive probes to explore the precise mechanism. In this work, we obtained compound , a mimic of , and biotin-labeled and fluorescein-based probes, which exhibited homologous biological activities to , including activating Nrf2 and its downstream target genes, anti-oxidative stress, and anti-inflammatory effects.

Discovery of 3,5-Dimethyl-4-Sulfonyl-1-Pyrrole-Based Myeloid Cell Leukemia 1 Inhibitors with High Affinity, Selectivity, and Oral Bioavailability.

Myeloid cell leukemia 1 (Mcl-1) protein is a key negative regulator of apoptosis, and developing Mcl-1 inhibitors has been an attractive strategy for cancer therapy. Herein, we describe the rational design, synthesis, and structure-activity relationship study of 3,5-dimethyl-4-sulfonyl-1-pyrrole-based compounds as Mcl-1 inhibitors. Stepwise optimizations of hit compound with primary Mcl-1 inhibition (52%@30 μM) led to the discovery of the most potent compound with high affinity ( = 0.

Design and synthesis of Grp94 selective inhibitors based on Phe199 induced fit mechanism and their anti-inflammatory effects.

Glucose-regulated protein 94 (Grp94), a member of the Heat shock protein 90 (Hsp90) family, is implicated in many human diseases, including cancer, neurodegeneration, inflammatory, and infectious diseases. Here, we describe our effort to design and develop a new series of Grp94 inhibitors based on Phe199 induced fit mechanism. Using an alkynyl-containing inhibitor as a starting point, we developed compound 4, which showed potent inhibitory activity toward Grp94 in a fluorescence polarization-based assay.

An affinity prediction approach for the ligand of E3 ligase Cbl-b and an insight into substrate binding pattern.

Protein-protein interactions (PPIs) are essentially fundamental to all cellular processes, so that developing small molecule inhibitors of PPIs have great significance despite representing a huge challenge. Studying PPIs with the help of peptide motifs could obtain the structural information and reference significance to reduce the difficulty in the development of small molecules. Computational methods are powerful tools to characterize peptide-protein interactions, especially molecular dynamics simulation and binding free energy calculation.

Regulation of Nrf2 by phosphorylation: Consequences for biological function and therapeutic implications.

The transcription factor nuclear factor erythroid-derived 2-like 2 (NRF2) participates in the activation of the antioxidant cytoprotective pathway and other important physiological processes to maintain cellular homeostasis. The dysregulation of NRF2 activity plays a role in various diseases, such as cardiovascular diseases, neurodegenerative diseases, and cancer. Thus, NRF2 activity is tightly regulated through multiple mechanisms, among which phosphorylation by kinases is critical in the posttranslational regulation of NRF2.

Agonist of stimulator of interferon genes as antitumor agents: a patent review (2008-2020).

Introduction: Stimulator of interferon genes (STING) is a transmembrane protein that localizes in the endoplasmic reticulum. As a crucial adaptor protein in the pathway of sensing cytosolic DNA, STING can regulate innate immune response by inducing the secretion of type Ι interferons and other cytokines after recognizing endogenous or exogenous DNA. Due to the key role of STING in the innate immune system, activation of the STING signaling pathway is expected to be an efficacious immunotherapeutic tactic for cancer and infectious diseases caused by pathogens.

Development of Novel Tetrahydroquinoline Inhibitors of NLRP3 Inflammasome for Potential Treatment of DSS-Induced Mouse Colitis.

The NLRP3 inflammasome is a critical component of innate immunity, which defends internal and external threats. However, inappropriate activation of the NLRP3 inflammasome induces various human diseases. In this study, we discovered and synthesized a series of tetrahydroquinoline inhibitors of NLRP3 inflammasome.

An updated patent review of anticancer Hsp90 inhibitors (2013-present).

Introduction: Heat shock protein 90 (Hsp90) is one of the most critical chaperones amenable to mediating the folding and maturation of more than 300 client proteins. In normal cells, Hsp90 chaperone cycle is required for regulating multiple cellular processes to maintain homeostasis. However, extremely overexpressed Hsp90 in neoplastic cells results in the dysregulation of client proteins, many of which are indispensable to the accumulation of cancer hallmarks, such as infinite proliferation and increased invasiveness.

Design, Synthesis, and Structure-Activity Relationships of Indoline-Based Kelch-like ECH-Associated Protein 1-Nuclear Factor (Erythroid-Derived 2)-Like 2 (Keap1-Nrf2) Protein-Protein Interaction Inhibitors.

The Keap1 (Kelch-like ECH-associated protein 1)-Nrf2 (nuclear factor erythroid 2-related factor 2)-ARE (antioxidant response element) pathway is the major defending mechanism against oxidative stresses, and directly disrupting the Keap1-Nrf2 protein-protein interaction (PPI) has been an attractive strategy to target oxidative stress-related diseases, including cardiovascular diseases. Here, we describe the design, synthesis, and structure-activity relationships (SARs) of indoline-based compounds as potent Keap1-Nrf2 PPI inhibitors. Comprehensive SAR analysis and thermodynamics-guided optimization identified as the most potent inhibitor in this series, with an IC of 22 nM in a competitive fluorescence polarization assay.

Discovery of 2-oxy-2-phenylacetic acid substituted naphthalene sulfonamide derivatives as potent KEAP1-NRF2 protein-protein interaction inhibitors for inflammatory conditions.

Nuclear factor erythroid 2-related factor 2 (NRF2) is a pleiotropic transcription factor which regulates the constitutive and inducible transcription of a wide array of genes and confers protection against a variety of pathologies. Directly disrupting Kelch-like ECH-associated protein 1 (KEAP1)-NRF2 protein-protein interaction (PPI) has been explored as a promising strategy to activate NRF2. We reported here the first identification of a series of 2-oxy-2-phenylacetic acid substituted naphthalene sulfonamide derivatives as potent KEAP1-NRF2 inhibitors.

Myeloid cell leukemin-1 inhibitors: a growing arsenal for cancer therapy.

B-cell lymphoma-2 (Bcl-2) family proteins, comprising proapoptotic proteins (Bax and Bak), antiapoptotic proteins (Bcl-2, Bcl-X, Bcl-w, Mcl-1, and A1) and BCL-2 homology domain 3 (BH3)-only proteins (Bid, Noxa, and Puma), have long been identified as pivotal apoptosis regulators. As an antiapoptotic member, myeloid cell leukemin-1 (Mcl-1) can bind with proapoptotic proteins and inhibit apoptosis. Mcl-1 is frequently overexpressed and closely associated with oncogenesis and poor prognosis in several cancers, posing a tremendous obstacle for cancer therapy.

Azo-PROTAC: Novel Light-Controlled Small-Molecule Tool for Protein Knockdown.

Reversibly altering endogenous protein levels are persistent issues. Herein, we designed photoswitchable azobenzene-proteolysis targeting chimeras (Azo-PROTACs) by including azobenzene moieties between ligands for the E3 ligase and the protein of interest. Azo-PROTACs are light-controlled small-molecule tools for protein knockdown in cells.

Proton pump inhibitors selectively suppress MLL rearranged leukemia cells via disrupting MLL1-WDR5 protein-protein interaction.

Genetic rearrangements of the mixed lineage leukemia (MLL) leading to oncogenic MLL-fusion proteins (MLL-FPs). MLL-FPs occur in about 10% of acute leukemias and are associated with dismal prognosis and treatment outcomes which emphasized the need for new therapeutic strategies. In present study, by a cell-based screening in-house compound collection, we disclosed that Rabeprazole specially inhibited the proliferation of leukemia cells harboring MLL-FPs with little toxicity to non-MLL cells.

Targeting Stimulator of Interferon Genes (STING): A Medicinal Chemistry Perspective.

Stimulator of interferon genes (STING) is an adaptor protein that induces the secretion of type I interferons and proinflammatory cytokines and is triggered by cytosolic DNA of pathogen and host origins. Given that STING is a mediator in the immune system, pharmacological modulation of STING has shown viable therapeutic effects for pathogen infection, cancer, and inflammatory diseases. In the past decade, the substantial development in this field has encouraged the discovery of STING modulators.