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Glutamine‐addicted cancer metabolism is recently recognized as novel cancer target especially for KRAS and KEAP1 co‐occurring mutations. To identify more drug‐like GLS inhibitors, we report the amides in the wing macrocycles for GLS inhibition with unique SAR analysis. Although the amidotriazoles (amides in the wing) are in general less potent than those of acylaminothiadiazole analogs (reverse amides in the wing), macrocycle 4, 5, and 7 are selected as a potent macrocyclic GLS inhibitor in both biochemical and cell viability assays. Selected molecules result in partial reduction in intracellular glutamate levels in LR (LDK378‐resistant) cells which is consistent to their cells viability result. Finally, selected compounds reduce the growth of A549 and H460 cells which have co‐occurring mutations including KRAS and KEAP1. The putative binding mode of macrocycle 4 is also suggested using a molecular docking model. [ABSTRACT FROM AUTHOR]

Background: Since severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) was first reported in Wuhan, China, in December 2019, it has spread rapidly, and many coronavirus disease (COVID‐19) cases have occurred in Gwangju, South Korea. Viral mutations following the COVID‐19 epidemic have increased interest in the characteristics of epidemics in this region, and pathogen genetic analysis is required for infection control and prevention. Methods: In this study, SARS‐CoV‐2 whole‐genome analysis was performed on samples from patients with COVID‐19 in Gwangju from 2020 to 2022 to identify the trends in COVID‐19 prevalence and to analyze the phylogenetic relationships of dominant variants. B.41 and B.1.497 prevailed in 2020, the early stage of the COVID‐19 outbreak; then, B.1.619.1 mainly occurred until June 2021. B.1.617.2, classified as sublineages AY.69 and AY.122, occurred continuously from July to December 2021. Since strict measures to strengthen national quarantine management had been implemented in South Korea until this time, the analysis of mutations was also able to infer the epidemiological relationship between infection transmission routes. Since the first identification of the Omicron variant in late December 2021, the spread of infection has been very rapid, and weekly whole‐genome analysis of specimens has enabled us to monitor new Omicron sublineages occurring in Gwangju. Conclusions: Our study suggests that conducting regional surveillance in addition to nation‐level genomic surveillance will enable more rapid and detailed variant surveillance, which will be helpful in the overall prevention and management of infectious diseases. [ABSTRACT FROM AUTHOR]

Death‐associated protein kinase‐related apoptosis‐inducing protein kinase 2 (DRAK2) has become a promising target for drug development. In search of novel and selective DRAK2 inhibitor motif, in vitro screen kinase assay was established performed using in‐house chemical libraries. After through hit triage procedure, N2‐(3,5‐dichlorophenyl)‐5‐fluoro‐N4‐methylpyrimidine‐2,4‐diamine (1) was selected as initial hit with structural novelty and drug‐likeness. During hit validation, structure–activity relationship of 1 was thoroughly disclosed and TRD‐93 was finally validated as hit for DRAK2 inhibition. TRD‐93 is small (mw = 290) but selectively potent to DRAK2 (IC50 = 0.16 μM) over other kinases including DAPK family kinases. Molecular binding model study of TRD‐93 to DRAK2 is also discussed. [ABSTRACT FROM AUTHOR]

Recently, there has been social controversy regarding whether benzimidazole anthelmintic drugs can be used as anticancer drugs. On this note, we wish to address the use of current benzimidazole anthelmintic drugs for the treatment of cancer patients. We explored the anticancer efficacy of benzimidazole anthelmintic drugs in vitro and their mechanism of action. We also conducted pharmacokinetic studies of two benzimidazole anthelmintics and assessed the predictive systemic efficacy. Finally, we present the anticancer efficacy of benzimidazole anthelmintics' putative metabolites from hydrolysis. Our data suggest that benzimidazole anthelmintic drugs are not expected to show systemic anticancer efficacy in vivo due to poor pharmacokinetic parameters. Therefore, patients should not consider oxibendazole or fenbendazole as cancer treatment option. [ABSTRACT FROM AUTHOR]

This work proposes the data augmentation by molecular rotation, with consideration that the protein‐ligand binding events are rotation‐variant. As a proof‐of‐concept, known active (i. e., 1‐labeled) ligands to human β‐secretase 1 (BACE‐1) are rotated for the generation of 0‐labeled data, and the rotation‐dependent prediction accuracy of 3D graph convolutional network (3DGCN) is investigated after data augmentation. The data augmentation makes the orientation‐recognizing ability of 3DGCN improved significantly in the classification task for BACE‐1/ligand binding. Furthermore, the data‐augmented 3DGCN has a capability for predicting active ligands from a candidate dataset, via improved performance of orientation recognition, which would be applied to virtual drug screening and discovery. [ABSTRACT FROM AUTHOR]

Apoptosis signal‐regulating kinase 1 (ASK1) is a member of mitogen‐activated protein kinase kinase kinase (MAP3K) family that involves downstream phosphorylation of MAP kinases, c‐Jun N‐terminal kinases, and p38 MAP kinases. ASK1 inhibitors could possibly be beneficial for ameliorating the development and progression of diseases. Especially, ASK1 has been of interest as one of therapeutic targets for nonalcoholic fatty liver disease as the most common chronic liver diseases including simple steatosis and nonalcoholic steatohepatitis. In this manuscript, novel ASK1 inhibitor lead KTA‐29 which has an imidazo[1,2‐b]pyridazine core with novel C6‐bicycloheptaneimidazole is disclosed. With the novel imidazo[1,2‐b]pyridazine core, structure‐activity‐relationship study for ASK1 potency is described and KTA‐29 affinity toward ASK1 with molecular modeling study is explained. [ABSTRACT FROM AUTHOR]

This work describes the process by which a metabolically unstable TRT‐0002 compound exhibiting Tumor necrosis factor‐related apoptosis‐inducing ligand (TRAIL)‐sensitizing activity for Huh7 cells at a high working concentration (40 μM) is converted to more potent and metabolically improved analogues by modifying the 5‐amino group and the 1‐aryl moiety in the 1H‐indazole skeleton. The efforts enabled us to identify 5‐sulfonamido derivatives, TRT‐0029 and TRT‐0173 compounds, working at lower concentrations (10 and 20 μM, respectively) and with improved metabolic stabilities. As reported previously by us, co‐treating cultured Huh7 cells with either TRT‐0029 or TRT‐0173 and TRAIL resulted in TRAIL‐induced apoptosis due to the inhibition of the MKK7–TOR signaling pathway regulator‐like (TIPRL) interaction and subsequent phosphorylation of MKK7 and JNK. In addition, the injection of TRT‐0029 or TRT‐0173 compound suppressed tumor growth in combination with TRAIL in an in vivo hepatocellular carcinoma (HCC) mouse xenograft model. TRT‐0029 and TRT‐0173 compounds and the relevant structure–activity relationship can provide an insight into further study on optimization of potency and metabolic stability. [ABSTRACT FROM AUTHOR]

This Letter presents a synthesisable phase rotator (PR) which operates without switching glitches that are reported in conventional implementations. The proposed conditionally cascading PR (CCPR) is comprised of two multiplexers (MUXes) with logic gates, and a phase interpolator (PI). This composition enables the automatic design flow through hardware description language which shortens the design time. With the MUXes operating as a cascaded PI at transition points, the proposed CCPR outputs a clock without any transient anomaly. A remarkable reduction in power and area is achieved by sharing a common PI for every pair of input clocks and merging low pass filters into the MUXes. Simulated in a 40‐nm technology, the proposed CCPR consumes 1.9 mW at a 1.1 V supply with 5.4 GHz operation. [ABSTRACT FROM AUTHOR]

DAP kinase-related apoptosis-inducing protein kinase 2 (DRAK2) is a member of the death-associated protein kinase (DAPK) family[1] and originally identified as a proapoptotic protein with the ability to induce apoptosis when overexpressed in various cell types.[2] However, the apoptosis-inducing ability of DRAK2 seems to be controversial and influenced by cellular factors within a specific cell types.[[3]] Recently, it has been suggested that DRAK2 is closely involved in tumorigenesis; DRAK2 expression was found to be highly elevated in multiple tumor types such as basal-like and HER2-enriched breast cancers. B Vertex-3 b is a pyrimidine C5-methylated analog of B UC-3 b .[9] When B UC-3 b was assessed to ATP-binding site of 359 diverse kinases at 10 micromolar concentration, it bound to 337 kinases including CDK2, CDK5, JNK3, and others. We believe the nitrile of the B UC-3 b has hydrogen-bonding interaction to DRAK2 Lys62 and plays a key role for its kinase promiscuous activities. [Extracted from the article]

The article focuses on a study which discussed the n-propyl tail effect to anaplastic lymphoma kinase (ALK) inhibition. Offered are information about nucleophosmin (NPM)-ALK fusion protein. Cited are several ALK inhibitors including the pyrimidine ALK inhibitors NVP-TAE684 and LDK378 or ceritinib. Also described is a general synthetic chemistry toward 2-anilino-4-(3,5-dicarboxamidespiperidine)-pyrimidines.

The article discusses the identification of tropomyosin receptor kinase A (TrkA) which encoded with the neurotrophic tyrosine receptor kinase 1 (NTRK1) gene. It examines the anti-apoptotic event of TrKA in the nerve growth factor (NGF) function. It also stresses the synthetic chemistry of chemicals towards limited structure-activity relationship of TrkA .

Front Cover: Rotational Variance-Based Data Augmentation in 3D Graph Convolutional Network (Chem. Keywords: Data augmentation; Deep learning; 3D Graph convolutional network; Protein-ligand binding; Rotational variance EN Data augmentation Deep learning 3D Graph convolutional network Protein-ligand binding Rotational variance 2568 2568 1 09/22/21 20210920 NES 210920 B Data augmentation for 3D graph convolutional network (3DGCN) b has been achieved, for the classification task of human -secretase 1 (BACE-1)-ligand binding, by randomly rotating known active (1-labeled) ligands in the 3D Cartesian coordinate and assigning the rotated ones as label-0. Data augmentation, Deep learning, 3D Graph convolutional network, Protein-ligand binding, Rotational variance. [Extracted from the article]