Risk of type 2 diabetes mellitus in adult patients with atopic dermatitis.

AIMS: This study aimed to investigate the subsequent risk of type 2 diabetes mellitus (T2D) in adults newly diagnosed with atopic dermatitis (AD). METHODS: This propensity score-matching cohort study used data from the National Health Insurance Service-National Sample Cohort (NHIS-NSC) 2.0 database in South Korea from 2002 to 2015. The adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated using a Cox proportional hazards model, for the new onset of T2D (ICD-10 code, E11) in AD patients compared to the matched controls. Subgroup and sensitivity analyses were also conducted. RESULTS: Each of the 36,692 individuals in the AD group and matched control group was included in the analysis. The risk of T2D in the AD group was significantly higher than that of the matched controls in the adjusted model (adjusted HR 1.44; 95% CI 1.27-1.63, P <.001). The results of subgroup analysis by sex, age, and body mass index were consistent with the results of the primary analysis. Sensitivity analyses using different T2D and/or AD definitions also showed consistent results. CONCLUSIONS: The significant risk of subsequent T2D in adult AD patients suggested the necessity for efforts to prevent T2D in AD patients.

Identification of a novel class of cortisol biosynthesis inhibitors and its implications in a therapeutic strategy for hypercortisolism.

AIMS: Dysregulation of adrenocortical steroid (corticosteroids) biosynthesis leads to pathological conditions such as Cushing's syndrome. Although several classes of steroid biosynthesis inhibitors have been developed to treat cortisol overproduction, limitations such as insufficient efficacy, adverse effects, and/or tolerability still remain. The present study aimed to develop a new class of small molecules that inhibit cortisol production, and investigated their putative modes of action. MAIN METHODS: We screened an in-house chemical library with drug-like chemical scaffolds using human adrenocortical NCI-H295R cells. We then evaluated and validated the effects of the selected compounds at multiple regulatory steps of the adrenal steroidogenic pathway. Finally, genome-wide RNA expression analysis coupled with gene enrichment analysis was conducted to infer possible action mechanisms. KEY FINDINGS: A subset of benzimidazolylurea derivatives, including a representative compound (designated as CJ28), inhibited both basal and stimulated production of cortisol and related intermediate steroids. CJ28 attenuated the mRNA expression of multiple genes involved in steroidogenesis and cholesterol biosynthesis. Furthermore, CJ28 significantly attenuated de novo cholesterol biosynthesis, which contributed to its suppression of cortisol production. SIGNIFICANCE: We identified a novel chemical scaffold that exerts inhibitory effects on cortisol and cholesterol biosynthesis via coordinated transcriptional silencing of gene expression networks. Our findings also reveal an additional adrenal-directed pharmacological strategy for hypercortisolism involving a combination of inhibitors targeting steroidogenesis and de novo cholesterol biosynthesis.

Synthesis and biological evaluation of flavonoid-based IP6K2 inhibitors.

Inositol polyphosphates (IPs) are a group of inositol metabolites that act as secondary messengers for external signalling cues. They play various physiological roles such as insulin release, telomere length maintenance, cell metabolism, and aging. Inositol hexakisphosphate kinase 2 (IP6K2) is a key enzyme that produces 5-diphosphoinositol 1,2,3,4,6-pentakisphosphate (5-IP7), which influences the early stages of glucose-induced exocytosis. Therefore, regulation of IP6Ks may serve as a promising strategy for treating diseases such as diabetes and obesity. In this study, we designed, synthesised, and evaluated flavonoid-based compounds as new inhibitors of IP6K2. Structure-activity relationship studies identified compound 20s as the most potent IP6K2 inhibitor with an IC50 value of 0.55 µM, making it 5-fold more potent than quercetin, the reported flavonoid-based IP6K2 inhibitor. Compound 20s showed higher inhibitory potency against IP6K2 than IP6K1 and IP6K3. Compound 20s can be utilised as a hit compound for further structural modifications of IP6K2 inhibitors.

Recent Advances in the Development of Antidepressants Targeting the Purinergic P2X7 Receptor.

The purinergic P2X7 receptor (P2X7R) is an adenosine triphosphate (ATP)- gated cation channel protein. Although extracellular ATP (eATP) is maintained at the nanomolar concentration range under normal conditions, it is elevated to micromolar levels in response to cell stress or damage, resulting in activation of P2X7R in the brain. The binding of eATP to P2X7R in glial cells in the brain activates the NLRP3 inflammasome and releases pro-inflammatory cytokines, such as IL-1ß, IL-6, IL-18, and TNFα. Depression has been demonstrated to be strongly associated with neuroinflammation activated by P2X7R. Therefore, P2X7R is an attractive therapeutic target for depression. Multinational pharmaceutical companies, including AstraZeneca, GlaxoSmithKline, Janssen, Lundbeck, and Pfizer, have developed CNS-penetrating P2RX7 antagonists. Several of these have been evaluated in clinical trials. This review summarizes the recent development of P2X7R antagonists as novel antidepressant agents in terms of structural optimization, as well as in vitro/in vivo evaluation and physicochemical properties of representative compounds.

Azumamides A-E: Isolation, Synthesis, Biological Activity, and Structure-Activity Relationship.

Cyclic peptides are one of the important chemical groups in the HDAC inhibitor family. Following the success of romidepsin in the clinic, naturally occurring cyclic peptides with a hydrophilic moiety have been intensively studied to test their function as HDAC inhibitors. Azumamides A-E, isolated from Mycale izuensis, are one of the powerful HDAC inhibitor classes. Structurally, azumamides A-E consist of three D-α-amino acids and unnatural ß-amino acids such as 3-amino-2-methyl-5-nonenedioic acid-9-amide (Amnna) and 3-amino-2-methyl-5-nonenoic-1,9-diacid (Amnda). Moreover, azumamides have a retro-arrangement peptide backbone, unlike other naturally occurring cyclopeptide HDAC inhibitors, owing to the D-configuration of all residues. This review summarizes the currently available synthetic methods of azumamides A-E focusing on the synthesis of ß-amino acids and macrocyclization. In addition, we overview the structure-activity relationship of azumamides A-E based on reported analogs. Collectively, this review highlights the potentiality of azumamides A-E as an HDAC inhibitor and provides further developmental insight into naturally occurring cyclic peptides in HDAC inhibition.

Serum and glucocorticoid-regulated kinase 1: Structure, biological functions, and its inhibitors.

Serum and glucocorticoid-regulated kinase 1 (SGK1) is a serine/threonine kinase belonging to the protein kinase A, G, and C (AGC) family. Upon initiation of the phosphoinositide 3-kinase (PI3K) signaling pathway, mammalian target of rapamycin complex 2 (mTORC2) and phosphoinositide-dependent protein kinase 1 (PDK1) phosphorylate the hydrophobic motif and kinase domain of SGK1, respectively, inducing SGK1 activation. SGK1 modulates essential cellular processes such as proliferation, survival, and apoptosis. Hence, dysregulated SGK1 expression can result in multiple diseases, including hypertension, cancer, autoimmunity, and neurodegenerative disorders. This review provides a current understanding of SGK1, particularly in sodium transport, cancer progression, and autoimmunity. In addition, we summarize the developmental status of SGK1 inhibitors, their structures, and respective potencies evaluated in pre-clinical experimental settings. Collectively, this review highlights the significance of SGK1 and proposes SGK1 inhibitors as potential drugs for treatment of clinically relevant diseases.

Synthesis of 7,2'-Dihydroxy-4',5'-Dimethoxyisoflavanone, a Phytoestrogen with Derma Papilla Cell Proliferative Activity.

This paper reports a concise and scalable method for the synthesis of the phytoestrogen 7,2'-dihydroxy-4',5'-dimethoxyisoflavanone 1 via an optimized synthetic route. Compound 1 was readily obtained in 11 steps and 11% overall yield on a gram scale from commercially available 3,4-dimethoxyphenol. The key features of the synthesis include the construction of the deoxybenzoin unit through a sequence of Claisen rearrangement, oxidative cleavage, and aryllithium addition and the efficient synthesis of the isoflavanone architecture from highly functionalized 2-hydroxyketone.

Prospect of ULK1 modulators in targeting regulatory T cells.

Regulatory T (Treg) cells play an instrumental role in coordinating immune homeostasis via potent inhibitory effects. Defects in Treg cells lead to autoimmunity, but an overwhelming proportion of Treg cells encourages cancer progression. Hence, targeting Treg cells has emerged as a promising approach for mitigating disease severity. Recent studies have revealed that kinases are a critical component for tuning the fate of Treg cells, but the entire network of Treg-modulating kinases is still unclear. Here, we propose that the autophagy-activating UNC-51-like kinase 1 (ULK1) is a candidate for Treg cell modulation. While accumulating evidence has highlighted the role of autophagy-related kinases in Treg cells, the ULK1-Treg cell axis is yet to be examined. In this review, we predicted the potential role of ULK1 in Treg cell modulation. Furthermore, we summarized current ULK1 activators and inhibitors that can be investigated as Treg-targeting strategies, which might have beneficial outcomes in autoimmunity and cancer.

Cell extraction method coupled with LC-QTOF MS/MS analysis for predicting neuroprotective compounds from Polygonum tinctorium.

The cell extraction method coupled with LC-QTOF-MS/MS is a biological screening technique in which cells are incubated with extracts of natural products, which results in potential bioactive compounds selectively combining with various extracellular and intracellular targets. Although the neuroprotective effects of the plant Polygonum tinctorium are unknown, the ethyl acetate (EtOAc) fraction exhibits significant neuroprotective effects against ʟ-glutamate-induced cytotoxicity in HT22 cells. In this study, we attempted to identify the neuroprotective compounds in the EtOAc fraction of P. tinctorium using the cell extraction method coupled with LC-QTOF MS/MS. Potential neuroprotective components derived from P. tinctorium were combined selectively with HT22 cells, and cell-derived metabolites were identified. A new flavonoid compound, 3,5,3',4'-tetrahydroxy-6,7-methylendioxyflavone-3-O-ß-ᴅ-glucopyranoside (1), and 14 known compounds (2-15), with compounds 2, 3, 8, 13, and 15 detected by the cell extraction method, were isolated from the EtOAc fraction of P. tinctorium. Compounds 2, 8, 12, and 14 showed strong neuroprotective effects, with compounds 2 and 14 identified in this plant for the first time in this study. Our results indicate that the cell extraction method coupled with LC-QTOF MS/MS is a useful tool for screening and identifying neuroprotective compounds in natural products.

Molecular basis for cooperative binding and synergy of ATP-site and allosteric EGFR inhibitors.

Lung cancer is frequently caused by activating mutations in the epidermal growth factor receptor (EGFR). Allosteric EGFR inhibitors offer promise as the next generation of therapeutics, as they are unaffected by common ATP-site resistance mutations and synergize with the drug osimertinib. Here, we examine combinations of ATP-competitive and allosteric inhibitors to better understand the molecular basis for synergy. We identify a subset of irreversible EGFR inhibitors that display positive binding cooperativity and synergy with the allosteric inhibitor JBJ-04-125-02 in several EGFR variants. Structural analysis of these complexes reveals conformational changes occur mainly in the phosphate-binding loop (P-loop). Mutation of F723 in the P-loop reduces cooperative binding and synergy, supporting a mechanism in which F723-mediated contacts between the P-loop and the allosteric inhibitor are critical for synergy. These structural and mechanistic insights will aid in the identification and development of additional inhibitor combinations with potential clinical value.

Quinazolinones as allosteric fourth-generation EGFR inhibitors for the treatment of NSCLC.

The C797S mutation confers resistance to covalent EGFR inhibitors used in the treatment of lung tumors with the activating L858R mutation. Isoindolinones such as JBJ-4-125-02 bind in an allosteric pocket and are active against this mutation, with high selectivity over wild-type EGFR. The most potent examples we developed from that series have a potential chemical instability risk from the combination of the amide and phenol groups. We explored a scaffold hopping approach to identify new series of allosteric EGFR inhibitors that retained good potency in the absence of the phenol group. The 5-F quinazolinone 34 demonstrated tumor regression in an H1975 efficacy model upon once daily oral dosing at 25 mg/kg.

An allosteric inhibitor against the therapy-resistant mutant forms of EGFR in non-small cell lung cancer.

Epidermal growth factor receptor (EGFR) therapy using small-molecule tyrosine kinase inhibitors (TKIs) is initially efficacious in patients with EGFR-mutant lung cancer, although drug resistance eventually develops. Allosteric EGFR inhibitors, which bind to a different EGFR site than existing ATP-competitive EGFR TKIs, have been developed as a strategy to overcome therapy-resistant EGFR mutations. Here we identify and characterize JBJ-09-063, a mutant-selective allosteric EGFR inhibitor that is effective across EGFR TKI-sensitive and resistant models, including those with EGFR T790M and C797S mutations. We further uncover that EGFR homo- or heterodimerization with other ERBB family members, as well as the EGFR L747S mutation, confers resistance to JBJ-09-063, but not to ATP-competitive EGFR TKIs. Overall, our studies highlight the potential clinical utility of JBJ-09-063 as a single agent or in combination with EGFR TKIs to define more effective strategies to treat EGFR-mutant lung cancer.

A Novel HER2-Selective Kinase Inhibitor Is Effective in HER2 Mutant and Amplified Non-Small Cell Lung Cancer.

In-frame insertions in exon 20 of HER2 are the most common HER2 mutations in patients with non-small cell lung cancer (NSCLC), a disease in which approved EGFR/HER2 tyrosine kinase inhibitors (TKI) display poor efficiency and undesirable side effects due to their strong inhibition of wild-type (WT) EGFR. Here, we report a HER2-selective covalent TKI, JBJ-08-178-01, that targets multiple HER2 activating mutations, including exon 20 insertions as well as amplification. JBJ-08-178-01 displayed strong selectivity toward HER2 mutants over WT EGFR compared with other EGFR/HER2 TKIs. Determination of the crystal structure of HER2 in complex with JBJ-08-178-01 suggests that an interaction between the inhibitor and Ser783 may be responsible for HER2 selectivity. The compound showed strong antitumoral activity in HER2-mutant or amplified cancers in vitro and in vivo. Treatment with JBJ-08-178-01 also led to a reduction in total HER2 by promoting proteasomal degradation of the receptor. Taken together, the dual activity of JBJ-08-178-01 as a selective inhibitor and destabilizer of HER2 represents a combination that may lead to better efficacy and tolerance in patients with NSCLC harboring HER2 genetic alterations or amplification. SIGNIFICANCE: This study describes unique mechanisms of action of a new mutant-selective HER2 kinase inhibitor that reduces both kinase activity and protein levels of HER2 in lung cancer.

Surveillance of avian influenza viruses from 2009 to 2013 in South Korea.

Avian influenza viruses (AIVs) are carried by wild migratory waterfowl across migratory flyways. To determine the strains of circulating AIVs that may pose a risk to poultry and humans, regular surveillance studies must be performed. Here, we report the surveillance of circulating AIVs in South Korea during the winter seasons of 2009-2013. A total of 126 AIVs were isolated from 7942 fecal samples from wild migratory birds, with a total isolation rate of 1.59%. H1‒H7 and H9‒H11 hemagglutinin (HA) subtypes, and N1‒N3, N5, and N7‒N9 neuraminidase (NA) subtypes were successfully isolated, with H6 and N2 as the most predominant HA and NA subtypes, respectively. Sequence identity search showed that the HA and NA genes of the isolates were highly similar to those of low-pathogenicity influenza strains from the East Asian-Australasian flyway. No match was found for the HA genes of high-pathogenicity influenza strains. Thus, the AIV strains circulating in wild migratory birds from 2009 to 2013 in South Korea likely had low pathogenicity. Continuous surveillance studies such as this one must be performed to identify potential precursors of influenza viruses that may threaten animal and human health.

Neural-Cadherin Influences the Homing of Terminally Differentiated Memory CD8 T Cells to the Lymph Nodes and Bone Marrow.

Memory T (TM) cells play an important role in the long-term defense against pathogen reinvasion. However, it is still unclear how these cells receive the crucial signals necessary for their longevity and homeostatic turnover. To understand how TM cells receive these signals, we infected mice with lymphocytic choriomeningitis virus (LCMV) and examined the expression sites of neural cadherin (N-cadherin) by immunofluorescence microscopy. We found that N-cadherin was expressed in the surroundings of the white pulps of the spleen and medulla of lymph nodes (LNs). Moreover, TM cells expressing high levels of killer cell lectin-like receptor G1 (KLRG1), a ligand of N-cadherin, were co-localized with N-cadherin+ cells in the spleen but not in LNs. We then blocked N-cadherin in vivo to investigate whether it regulates the formation or function of TM cells. The numbers of CD127hiCD62Lhi TM cells in the spleen of memory P14 chimeric mice declined when N-cadherin was blocked during the contraction phase, without functional impairment of these cells. In addition, when CD127loKLRG1hi TM cells were adoptively transferred into anti-N-cadherin-treated mice compared with control mice, the number of these cells was reduced in the bone marrow and LNs, without functional loss. Taken together, our results suggest that N-cadherin participates in the development of CD127hiCD62Lhi TM cells and homing of CD127loKLRG1hi TM cells to lymphoid organs.

A Review of the Pharmacological Activities and Recent Synthetic Advances of γ-Butyrolactones.

γ-Butyrolactone, a five-membered lactone moiety, is one of the privileged structures of diverse natural products and biologically active small molecules. Because of their broad spectrum of biological and pharmacological activities, synthetic methods for γ-butyrolactones have received significant attention from synthetic and medicinal chemists for decades. Recently, new developments and improvements in traditional methods have been reported by considering synthetic efficiency, feasibility, and green chemistry. In this review, the pharmacological activities of natural and synthetic γ-butyrolactones are described, including their structures and bioassay methods. Mainly, we summarize recent advances, occurring during the past decade, in the construction of γ-butyrolactone classified based on the bond formation in γ-butyrolactone between (i) C5-O1 bond, (ii) C4-C5 and C2-O1 bonds, (iii) C3-C4 and C2-O1 bonds, (iv) C3-C4 and C5-O1 bonds, (v) C2-C3 and C2-O1 bonds, (vi) C3-C4 bond, and (vii) C2-O1 bond. In addition, the application to the total synthesis of natural products bearing γ-butyrolactone scaffolds is described.

Inhibitors of prostate-specific membrane antigen in the diagnosis and therapy of metastatic prostate cancer - a review of patent literature.

INTRODUCTION: Prostate-specific membrane antigen (PSMA), also known as glutamate carboxypeptidase II, is a potential target protein for imaging and treatment of patients with prostate cancer because of its overexpression during metastasis. Various PSMA-targeted imaging and therapeutic probes have been designed and synthesized based on the Lys-urea-Glu motif. Structural modifications have been made exclusively in the linker region, while maintaining the Lys-urea-Glu structure that interacts with S1 and S1' pockets. AREA COVERED: This review includes WIPO-listed patents (from January 2017 to June 2020) reporting PSMA-targeted probes based on the Lys-urea-Glu or Glu-urea-Glu structure. EXPERT OPINION: : PSMA-targeted imaging agents labeled with radionuclides such as fluorine-18, copper-64, gallium-68, and technetium-99m have been successfully translated into clinical phase for the early diagnosis of metastatic prostate cancer. Recently, PSMA-targeted therapeutic agents labeled with iodine-131, lutetium-177, astatine-211, and lead-212 have also been developed with notable progress. Most PSMA-targeted agents are based on the Lys-urea-Glu or Glu-urea-Glu structure, demonstrate strong PSMA-binding affinity in nanomolar range, and achieve diverse structural modifications in the non-pharmacophore pocket. By exploiting the S1 accessory pocket or the tunnel region of the PSMA active site, the in vivo efficacy and pharmacokinetic profiles of the PMSA-targeted agents can be effectively modulated.

Structure-activity relationship studies of dipeptide-based hepsin inhibitors with Arg bioisosteres.

Hepsin is a type II transmembrane serine protease (TTSP) associated with cell proliferation and overexpressed in several types of cancer including prostate cancer (PCa). Because of its significant role in cancer progression and metastasis, hepsin is an attractive protein as a potential therapeutic and diagnostic biomarker for PCa. Based on the reported Leu-Arg dipeptide-based hepsin inhibitors, we performed structural modification and determined in vitro hepsin- and matriptase-inhibitory activities. Comprehensive structure-activity relationship studies identified that the p-guanidinophenylalanine-based dipeptide analog 22a exhibited a strong hepsin-inhibitory activity (Ki = 50.5 nM) and 22-fold hepsin selectivity over matriptase. Compound 22a could be a prototype molecule for structural optimization of dipeptide-based hepsin inhibitors.

Visible-Light-Induced Cysteine-Specific Bioconjugation: Biocompatible Thiol-Ene Click Chemistry.

Bioconjugation methods using visible-light photocatalysis have emerged as powerful synthetic tools for the selective modification of biomolecules under mild reaction conditions. However, the number of photochemical transformations that allow successful protein bioconjugation is still limited because of the need for stringent reaction conditions. Herein, we report that a newly developed water-compatible fluorescent photosensitizer QPEG can be used for visible-light-induced cysteine-specific bioconjugation for the installation of QPEG by exploiting its intrinsic photosensitizing ability to activate the S-H bond of cysteine. The slightly modified QCAT enables the effective photocatalytic cysteine-specific conjugation of biologically relevant groups. The superior reactivity and cysteine selectivity of this methodology was further corroborated by traceless bioconjugation with a series of complex peptides and proteins under biocompatible conditions.

Mutant-Selective Allosteric EGFR Degraders are Effective Against a Broad Range of Drug-Resistant Mutations.

Targeting epidermal growth factor receptor (EGFR) through an allosteric mechanism provides a potential therapeutic strategy to overcome drug-resistant EGFR mutations that emerge within the ATP binding site. Here, we develop an allosteric EGFR degrader, DDC-01-163, which can selectively inhibit the proliferation of L858R/T790M (L/T) mutant Ba/F3 cells while leaving wildtype EGFR Ba/F3 cells unaffected. DDC-01-163 is also effective against osimertinib-resistant cells with L/T/C797S and L/T/L718Q EGFR mutations. When combined with an ATP-site EGFR inhibitor, osimertinib, the anti-proliferative activity of DDC-01-163 against L858R/T790M EGFR-Ba/F3 cells is enhanced. Collectively, DDC-01-163 is a promising allosteric EGFR degrader with selective activity against various clinically relevant EGFR mutants as a single agent and when combined with an ATP-site inhibitor. Our data suggests that targeted protein degradation is a promising drug development approach for mutant EGFR.