Boronic Acid-Containing 3- pyrazolo[4,3-]quinoline Compounds as Dual CLK/ROCK Inhibitors with Anticancer Properties.

The protein kinases CLK and ROCK play key roles in cell growth and migration, respectively, and are potential anticancer targets. ROCK inhibitors have been approved by the FDA for various diseases and CLK inhibitors are currently being trialed in the clinic as anticancer agents. Compounds with polypharmacology are desired, especially in oncology, due to the potential for high efficacy as well as addressing resistance issues.

Activation of cellular responses by cyclic dinucleotides and lipopolysaccharide: a proteomic study on gingival fibroblasts.

Background: Bacterial cyclic dinucleotides (CDNs), cyclic di-guanosine monophosphate (c-di-GMP), and cyclic di-adenosine monophosphate (c-di-AMP) upregulate interferon signaling proteins of human gingival fibroblasts (HGFs). However, the simultaneous effect of bacterial CDNs and lipopolysaccharides (LPS) on the HGF proteome is unknown.

Aim: The aim was to apply an unbiased proteomics approach to evaluate how simultaneous exposure to CDNs and (Pg) LPS affect the global proteome of HGFs.

Orally bioavailable STING antagonist synthesized multi-component Povarov-Doebner type reaction.

Aberrant activation of the cGAS-STING signaling results in innate immune response induction. Herein, we report HSKB142, an orally bioavailable compound containing the 3H-pyrazolo [4,3-]quinoline synthesized a Povarov-Doebner MCR. HSKB142 is non-cytotoxic towards immune cells and suppresses type-1 interferon expression in human THP-1 monocytes upon treatment with 2'3'-cGAMP.

Secretes c-di-AMP as an Extracellular Pathogen-Associated Molecular Pattern to Elicit Type I Interferon Responses in Mammalian Hosts.

(), an extracellular spirochetal pathogen, elicits a type-I interferon (IFN-I) response that contributes to the pathology of Lyme disease, including the development and severity of Lyme arthritis. However, the specific Pathogen-Associated Molecular Patterns (PAMPs) of responsible for triggering the IFN-I response are not well understood. Previous studies have identified an unknown, nuclease-resistant component in culture supernatants that significantly stimulates the IFN-I response, but its identity remains unknown.

Non-kinase off-target inhibitory activities of clinically-relevant kinase inhibitors.

Protein kinases are responsible for a myriad of cellular functions, such as cell cycle, apoptosis, and proliferation. Because of this, kinases make excellent targets for therapeutics. During the process to identify clinical kinase inhibitor candidates, kinase selectivity profiles of lead inhibitors are typically obtained.

PDE-stable 2'3'-cGAMP analogues, containing 5'-S-phosphorothioester linkage, as STING agonists.

The stimulator of interferon genes (STING) has emerged as a promising target for cancer immunotherapy. 2'3'-cGAMP, a natural agonist of STING, shows anticancer activity stimulation of immune cells but it is susceptible to degradation by hydrolytic enzymes. Consequently, the cyclic dinucleotide analogues that are being evaluated in the clinic as immunotherapies contain the hydrolytically stable phosphorothioate moiety, whereby the sulfur moiety is exo to the phosphate containing ring.

2',4'-LNA-Functionalized 5'-S-Phosphorothioester CDNs as STING Agonists.

Cyclic dinucleotides (CDNs) have garnered popularity over the last decade as immunotherapeutic agents, which activate the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway to trigger an immune response. Many analogs of 2'3'-cGAMP, c-di-GMP, and c-di-AMP have been developed and shown as effective cancer vaccines and immunomodulators for the induction of both the adaptive and innate immune systems. Unfortunately, the effectiveness of these CDNs is limited by their chemical and enzymatic instability.

Chloride Homeostasis Regulates cGAS-STING Signaling.

The cGAS-STING signaling pathway has emerged as a key mediator of inflammation. However, the roles of chloride homeostasis on this pathway are unclear. Here, we uncovered a correlation between chloride homeostasis and cGAS-STING signaling.

Identification and characterization of a potent and selective HUNK inhibitor for treatment of HER2+ breast cancer.

Human epidermal growth factor receptor 2 (HER2)-targeted agents have proven to be effective, however, the development of resistance to these agents has become an obstacle in treating HER2+ breast cancer. Evidence implicates HUNK as an anti-cancer target for primary and resistant HER2+ breast cancers. In this study, a selective inhibitor of HUNK is characterized alongside a phosphorylation event in a downstream substrate of HUNK as a marker for HUNK activity in HER2+ breast cancer.

Discovery of imidazo[1,2-]pyridazine-containing TAK1 kinase inhibitors with excellent activities against multiple myeloma.

Current treatment options for patients with multiple myeloma (MM) include proteasome inhibitors, anti-CD38 antibodies, and immunomodulatory agents. However, if patients have continued disease progression after administration of these treatments, there are limited options. There is a need for effective targeted therapies of MM.

Dual FLT3/haspin kinase inhibitor based on 3-pyrazolo[4,3-]quinoline scaffold with activities against acute myeloid leukemia.

The 3-pyrazolo[4,3-]quinoline core, a privileged fusion moiety from quinoline and indazole, facilely synthesized in a one flask multi-component Doebner-Povarov reaction, is a newly described kinase hinge binder. Previous works have demonstrated that the 3-pyrazolo[4,3-]quinoline moiety can be tuned, judicious substitution patterns, to selectively inhibit cancer-associated kinases, such as FLT3 and haspin. A first generation 3-pyrazolo[4,3-]quinoline-based haspin inhibitor, HSD972, and FLT3 inhibitor, HSD1169, were previously disclosed as inhibitors of various cancer cell lines.

Engineered Vancomycin, with Increased Interactions with Peptidoglycan Stem Peptide, Conquers Non-tuberculosis Mycobacteria.

Vancomycin-like drugs target peptidoglycan (PG) via binding to C-terminal d-Ala-d-Ala dipeptide. An engineered vancomycin has enhanced affinity for the PG stem peptide, due to probable interactions with a third residue, -diaminopimelic acid, in the PG. This engineered vancomycin displays enhanced killing of mycobacteria.

STING antagonists, synthesized Povarov-Doebner type multicomponent reaction.

The cGAS-STING axis plays an important role in protecting higher organisms against invading pathogens or cancer by promoting the production of cytokines and interferons. However, persistent or uncontrolled activation of this pathway could lead to inflamed environments, which is detrimental to the host in the long run. Persistent activation of STING is known to be the cause of STING-associated vasculopathy with onset in infancy (SAVI) and activated STING is believed to play important roles in worsening various diseased states, such as traumatic brain injury, diabetic kidney disease and colitis.

Targeting RET Solvent-Front Mutants with Alkynyl Nicotinamide-Based Inhibitors.

Selpercatinib (LOXO292) and pralsetinib (BLU667) are RET protein tyrosine kinase inhibitors (TKIs) recently approved for treating RET-altered cancers. However, RET mutations that confer selpercatinib/pralsetinib resistance have been identified, necessitating development of next-generation RET TKIs. While acquired RET G810C/R/S/V mutations were reported in selpercatinib-treated patients, it was unclear whether all of these and other potential G810 mutants are resistant to selpercatinib and pralsetinib.

Proteomic and phosphoproteomic analyses of Jurkat T-cell treated with 2'3' cGAMP reveals various signaling axes impacted by cyclic dinucleotides.

Cyclic dinucleotides (CDNs), such as 2'3'-cGAMP, bind to STING to trigger the production of cytokines and interferons, mainly via activation of TBK1. STING activation by CDN also leads to the release and activation of Nuclear Factor Kappa-light-chain-enhancer of activated B cells (NF-κB) via the phosphorylation of Inhibitor of NF-κB (IκB)-alpha (IκBα) by IκB Kinase (IKK). Beyond the canonical TBK1 or IKK phosphorylations, little is known about how CDNs broadly affect the phosphoproteome and/or other signaling axes.

Re-sensitization of Multidrug-Resistant and Colistin-Resistant Gram-Negative Bacteria to Colistin by Povarov/Doebner-Derived Compounds.

Colistin, typically viewed as the antibiotic of last resort to treat infections caused by multidrug-resistant (MDR) Gram-negative bacteria, had fallen out of favor due to toxicity issues. The recent increase in clinical usage of colistin has resulted in colistin-resistant isolates becoming more common. To counter this threat, we have investigated previously reported compounds, and , and developed 13 compounds with more desirable drug-like properties for colistin sensitization against 16 colistin-resistant bacterial strains, three of which harbor the plasmid-borne mobile colistin resistance ().

RET aberrant cancers and RET inhibitor therapies: Current state-of-the-art and future perspectives.

Precision oncology informed by genomic information has evolved in leaps and bounds over the last decade. Although non-small cell lung cancer (NSCLC) has moved to center-stage as the poster child of precision oncology, multiple targetable genomic alterations have been identified in various cancer types. RET alterations occur in roughly 2% of all human cancers.

Isoquinoline Antimicrobial Agent: Activity against Intracellular Bacteria and Effect on Global Bacterial Proteome.

A new class of alkynyl isoquinoline antibacterial compounds, synthesized via Sonogashira coupling, with strong bactericidal activity against a plethora of Gram-positive bacteria including methicillin- and vancomycin-resistant strains is presented. HSN584 and HSN739, representative compounds in this class, reduce methicillin-resistant (MRSA) load in macrophages, whilst vancomycin, a drug of choice for MRSA infections, was unable to clear intracellular MRSA. Additionally, both HSN584 and HSN739 exhibited a low propensity to develop resistance.

Bacterial chemotaxis in static gradients quantified in a biopolymer membrane-integrated microfluidic platform.

Chemotaxis is a fundamental bacterial response mechanism to changes in chemical gradients of specific molecules known as chemoattractant or chemorepellent. The advancement of biological platforms for bacterial chemotaxis research is of significant interest for a wide range of biological and environmental studies. Many microfluidic devices have been developed for its study, but challenges still remain that can obscure analysis.

Membrane acting Povarov-Doebner derived compounds potently disperse preformed multidrug resistant Gram-positive bacterial biofilms.

The National Institute of Health (NIH) estimates that the majority of human microbial infections are either linked to or directly caused by bacterial biofilms and these infections are immune to most currently approved FDA drugs. Hence, there is a need for the development of potent antibiotics against biofilms. We have previously shown that pentafluorosulfanyl (SF)-containing quinoline compounds, which were synthesized via the Povarov reaction, kill persister bacteria (Onyedibe et al.

Mechanistic Studies and Efficacy of an Oxadiazole-Containing Antibiotic.

Methicillin-resistant (MRSA) infections are still difficult to treat, despite the availability of many FDA-approved antibiotics. Thus, new compound scaffolds are still needed to treat MRSA. The oxadiazole-containing compound, , has been shown to reduce lipoteichoic acid (LTA) in , but the mechanism that accounts for LTA biosynthesis inhibition remains uncharacterized.

Comparative Studies to Uncover Mechanisms of Action of -(1,3,4-Oxadiazol-2-yl)benzamide Containing Antibacterial Agents.

Drug-resistant bacterial pathogens still cause high levels of mortality annually despite the availability of many antibiotics. Methicillin-resistant (MRSA) is especially problematic, and the rise in resistance to front-line treatments like vancomycin and linezolid calls for new chemical modalities to treat chronic and relapsing MRSA infections. Halogenated -(1,3,4-oxadiazol-2-yl)benzamides are an interesting class of antimicrobial agents, which have been described by multiple groups to be effective against different bacterial pathogens.