Discovery of 18F Labeled AZD5213 Derivatives as Novel Positron Emission Tomography (PET) Radioligands Targeting Histamine Subtype-3 Receptor.

The histamine subtype 3 (H3) receptor is an important drug target in the central nervous system (CNS), and PET imaging offers a promising technique for the noninvasive evaluation of CNS disease related to the H3 receptor. In this study, we synthesized and evaluated the binding effects of [18F]H3-2404 and [18F]H3-2405 by modifying the structure of AZD5213, a selective H3 antagonist. These two radioligands were prepared in high radiochemical yields and displayed stability in serum. The in vitro autoradiographic study in rat brain tissue and the following in vivo PET studies in mice demonstrated sufficient brain uptake but predominantly non-specific distribution in rodent brain. Although these data suggest that [18F]H3-2404 and [18F]H3-2405 are unsuitable as PET tracers for brain imaging of the H3 receptor, this study provides a valuable attempt for optimizing 18F labeled radiotracers based on AZD5213.

Preclinical Evaluation of Azabenzimidazole-Based PET Radioligands for γ-8 Dependent Transmembrane AMPA Receptor Regulatory Protein Imaging.

AMPA glutamate receptors (AMPARs) play a pivotal role in excitatory neurotransmission, particularly in the hippocampus where the TARP γ-8 subunit is enriched and serves as a target for emerging anti-epileptic drugs. To enable in vivo visualization of TARP γ-8 distribution and expression by positron emission tomography (PET), this study focuses on the development of novel 18 F-labeled TARP γ-8 inhibitors and their corresponding precursors, stemming from the azabenzimidazole scaffold. The resulting radioligands [18 F]TARP-2204 and [18 F]TARP-2205 were successfully synthesized with acceptable radiochemical yield, high molar activity, and excellent radiochemical purity. In vitro autoradiography demonstrates high level of specific binding of [18 F]TARP-2205 to TARP γ-8 in both rat and nonhuman primate brain tissues. However, unexpected radiodefluorination in PET imaging studies of rodents emphasizes the need for further structural refinement. This work serves as an excellent starting point for the development of future 18 F-labeled TARP γ-8 PET tracers, offering valuable insights into medicinal chemistry design, radiosynthesis and subsequent PET evaluation.

Discovery of novel indazole derivatives as SOS1 agonists that activate KRAS signaling.

KRAS serves as a vital regulator for cellular signaling and drives tumor pathogenesis after mutation. Despite extensive research efforts spanning several decades, targeting KRAS is still challenging due to the multiple KRAS mutations and the emergence of drug resistance. Interfering the interactions between KRAS and SOS1 is one of the promising approaches for modulating KRAS functions. Herein, we discovered small-molecule SOS1 agonists with novel indazole scaffold. Through structure-based optimization, compound 11 was identified with high SOS1 activation potency (p-ERK EC50 = 1.53 µM). In HeLa cells, compound 11 enhances cellular RAS-GTP levels and exhibits biphasic modulation of ERK1/2 phosphorylation through an on-target mechanism and presents the therapeutic potential to modulate RAS signaling by activating SOS1.

Synthesis and biological evaluation of azole-diphenylpyrimidine derivatives (AzDPPYs) as potent T790M mutant form of epidermal growth factor receptor inhibitors.

A series of novel azole-diphenylpyrimidine derivatives (AzDPPYs) were synthesized and biologically evaluated as potent EGFRT790M inhibitors. Among these analogues, the most active inhibitor 6e not only displayed high activity against EGFRT790M/L858R kinase (IC50=3.3nM), but also was able to repress the replication of H1975 cells harboring EGFRT790M mutation at a concentration of 0.118µmol/L. In contrast to the lead compound rociletinib, 6e slightly reduces the key EGFRT790M-minduced drug resistance. Significantly, inhibitor 6e demonstrates high selectivity (SI=299.3) for T790M-containing EGFR mutants over wild type EGFR, hinting that it will cause less side effects.

Novel Selective and Potent EGFR Inhibitor that Overcomes T790M-Mediated Resistance in Non-Small Cell Lung Cancer.

Treating patients suffering from EGFR mutant non-small cell lung cancer (NSCLC) with first-generation EGFR tyrosine kinase inhibitors (EGFR TKI) provides excellent response rates. However, approximately 60% of all patients ultimately develop drug resistance due to a second T790M EGFR TKI mutation. In this study, we report the novel molecule N-(3-((5-chloro-2-(4-((1-morpholino)methyl)phenylamino)-4-pyrimidinyl)amino)phenyl)acrylamide (DY3002) to preferentially inhibit the EGFR T790M mutant (EGFRT790M) (IC50 = 0.71 nM) over wild-type EGFR (IC50 = 448.7 nM) in kinase assays. Compared to rociletinib (SI = 21.4) and osimertinib (SI = 40.9), it significantly increased selectivity (SI = 632.0) against EGFRT790M over wild-type EGFR. Furthermore, in cell-based tests, DY3002, with an IC50 value of 0.037 µM, exhibited enhanced inhibitory potency against H1975 cells. Moreover, AO/EB and DAPI staining assays as well as flow cytometer analyses indicated that DY3002 possesses superior biological properties compared to alternatives. In addition, a rat oral glucose tolerance test revealed that treatment with high drug doses (50 mg/kg) of DY3002 did not result in hyperglycemia, suggesting a reduction of side effects in NSCLC patients will be achievable relative to established EGFR inhibitors. In summary, our findings indicate DY3002 as a promising preclinical candidate for effective treatment of patients with EGFRT790M-mutated NSCLC.

Improving automatic segmentation of liver tumor images using a deep learning model.

Liver tumors are one of the most aggressive malignancies in the human body. Computer-aided technology and liver interventional surgery are effective in the prediction, identification and management of liver neoplasms. One of the important processes is to accurately grasp the morphological structure of the liver and liver blood vessels. However, accurate identification and segmentation of hepatic blood vessels in CT images poses a formidable challenge. Manually locating and segmenting liver vessels in CT images is time-consuming and impractical. There is an imperative clinical requirement for a precise and effective algorithm to segment liver vessels. In response to this demand, the current paper advocates a liver vessel segmentation approach that employs an enhanced 3D fully convolutional neural network V-Net. The network model improves the basic network structure according to the characteristics of liver vessels. First, a pyramidal convolution block is introduced between the encoder and decoder of the network to improve the network localization ability. Then, multi-resolution deep supervision is introduced in the network, resulting in more robust segmentation. Finally, by fusing feature maps of different resolutions, the overall segmentation result is predicted. Evaluation experiments on public datasets demonstrate that our improved scheme can increase the segmentation ability of existing network models for liver vessels. Compared with the existing work, the experimental outcomes demonstrate that the technique presented in this manuscript has attained superior performance on the Dice Coefficient index, which can promote the treatment of liver tumors.

Surface Electromyography-Based Recognition of Electronic Taste Sensations.

Taste sensation recognition is a core for taste-related queries. Most prior research has been devoted to recognizing the basic taste sensations using the Brain-Computer Interface (BCI), which includes EEG, MEG, EMG, and fMRI. This research aims to recognize electronic taste (E-Taste) sensations based on surface electromyography (sEMG). Silver electrodes with platinum plating of the E-Taste device were placed on the tongue's tip to stimulate various tastes and flavors. In contrast, the electrodes of the sEMG were placed on facial muscles to collect the data. The dataset was organized and preprocessed, and a random forest classifier was applied, giving a five-fold accuracy of 70.43%. The random forest classifier was used on each participant dataset individually and in groups, providing the highest accuracy of 84.79% for a single participant. Moreover, various feature combinations were extracted and acquired 72.56% accuracy after extracting eight features. For a future perspective, this research offers guidance for electronic taste recognition based on sEMG.

The LINC01176-miR-218-5p-IL-36G Network is Responsible for the Pathogenesis of Psoriasis by Promoting Inflammation.

Purpose: Psoriasis is an incurable chronic inflammatory skin disease. The exact function and regulatory mechanism of non-coding RNA upregulation in psoriasis remains to be elucidated. The aim of this study was to analyse the role of the lncRNA-miRNA-mRNA network of psoriasis and LINC01176 in the pathogenesis of psoriasis. Patients and Methods: We performed miRNA, lncRNA, and mRNA sequencing analysis in pretreatment and treatment psoriatic tissues and normal tissues, constructed an lncRNA-miRNA-mRNA coexpression network and screened mRNA-associated pathways using bioinformatics analysis. We further validated the regulatory role of LINC01176-miR-218-5p on the proliferation and inflammation of the psoriatic model by dual-luciferase reporter assay, cell transfection, CCK-8 method, TUNEL staining and animal model construction method. An lncRNA-miRNA-mRNA coexpression network was successfully constructed by RNA-seq data analysis. Results: We obtained the relationship between LINC01176, miR-218-5p and IL36-G. Analysis of the apoptotic and proliferative capacity of the transfected cells showed that miR-218-5p up-regulation significantly inhibited cell proliferation and promoted apoptosis. A mouse model of psoriasis was successfully established. Phenotypic observations revealed that keratin-forming cells in mice coated with LINC01176-shRNA emulsifier were significantly lower than those in the model group and close to those in the normal group. HE and immunohistochemical experiments were performed, and the results showed the role and mechanism of action of LINC01176-shRNA. Suppression of LINC01176 significantly inhibited the expression of IL-36G in psoriatic tissues. LINC01176 showed a targeting and positive correlation with IL36-G expression. Conclusion: Our study shows that LINC01176 promotes the proliferation and invasion of keratinocytes and inhibits apoptosis by targeting miR-218-5p, which acts as a repressor of the psoriasis-associated IL-36G. The shRNA-LINC01176 emulsion showed potential treatment capability in alleviating symptoms of psoriasis.

Preclinical Evaluation of Novel Positron Emission Tomography (PET) Probes for Imaging Leucine-Rich Repeat Kinase 2 (LRRK2).

Parkinson's disease (PD) is one of the most highly debilitating neurodegenerative disorders, which affects millions of people worldwide, and leucine-rich repeat kinase 2 (LRRK2) mutations have been involved in the pathogenesis of PD. Developing a potent LRRK2 positron emission tomography (PET) tracer would allow for in vivo visualization of LRRK2 distribution and expression in PD patients. In this work, we present the facile synthesis of two potent and selective LRRK2 radioligands [11C]3 ([11C]PF-06447475) and [18F]4 ([18F]PF-06455943). Both radioligands exhibited favorable brain uptake and specific bindings in rodent autoradiography and PET imaging studies. More importantly, [18F]4 demonstrated significantly higher brain uptake in the transgenic LRRK2-G2019S mutant and lipopolysaccharide (LPS)-injected mouse models. This work may serve as a roadmap for the future design of potent LRRK2 PET tracers.

Radiosynthesis and Evaluation of 11C-Labeled Isoindolone-Based Positive Allosteric Modulators for Positron Emission Tomography Imaging of Metabotropic Glutamate Receptor 2.

The metabotropic glutamate receptor 2 (mGluR2) has emerged as a potential therapeutic target for the treatment of various neurological diseases, prompting substantial interest in the development of mGluR2-targeted drug candidates. As part of our medicinal chemistry program, we synthesized a series of isoindolone derivatives and assessed their potential as mGluR2 positive allosteric modulators (PAMs). Notably, AZ12559322 exhibited high affinity (K i mGluR2 = 1.31 nM) and an excellent in vitro binding specificity of 89% while demonstrating selectivity over other mGluR subtypes (>4000-fold). Autoradiography with the radiolabeled counterpart, [3H]AZ12559322, revealed a heterogeneous accumulation with the highest binding in mGluR2-rich brain regions. Radioligand binding was significantly reduced by pretreatment with nonradioactive mGluR2 PAMs in brains of rats and nonhuman primates. Although positron emission tomography imaging of [11C]AZ12559322 (6a) revealed low brain uptake in a nonhuman primate, this study provides valuable guidance to further design novel isoindolone-based mGluR2 PAMs with improved brain exposure.

Simulation study on assist-as-needed control of a rehabilitation robotic walker.

BACKGROUND: Along with China entering an aging society, the percentage of people that over 60 will reach 34.9% in 2050, resulted in a significant increase in stroke patients. OBJECTIVE: This paper proposes a rehabilitation robotic walker for walking assistance during the daily life, and a control method for the motor relearning during the gait training. The walker consists of an omni-directional mobile platform (OMP) which ensures the walker can move on the ground, a body weight support system (BWS) which is capable of providing the desired unloading force, and a pelvic assist mechanism (PAM) to provide the user with four degrees of freedom and avoid the rigid impact. The study goal is to gain a better understanding of the assist-as-needed control strategy during the gait training. METHODS: For the man-machine interaction control, the assist-as-needed control strategy is adopted to guide the users' motions and improve the interaction experience. To build the force field in the three-dimensional space, the dynamics of the system is derived to increase the accuracy of force control. RESULTS: The simulation results show that the force field around the motion trajectory was generated in the three-dimensional space. In order to understand the force field, we designed the simulation on sagittal plane and the controller can generate the appropriate force field. The preliminary experiment results were consistent with the simulation results. CONCLUSION: Based on the mathematical simulation and the preliminary test, the results demonstrate that the proposed system can provide the guide force around the target trajectory, the accuracy of force control still remains to be improved.

Identification of novel Pyrrolo[2,3-d]Pyrimidine-based KRAS G12C inhibitors with anticancer effects.

Oncogene KRAS plays predominant roles in human cancers by regulating cell proliferation, differentiation, and migration. Recent progress revealed that directly target KRAS G12C with allosteric inhibitors that covalently bind to the switch Ⅱ pocket is feasible. Herein, series of pyrrolo[2,3-d]pyrimidine derivatives were designed and synthesized through systematic structural optimization, leading to the discovery of compound 2-((S)-1-acryloyl-4-(2-(((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-7-methyl-6-(8-methylnaphthalen-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-2-yl)acetonitrile (50) with high KRAS/SOS1 inhibitory potency (IC50 = 0.21 µM) and strong anti-proliferation activities on cancer cells harboring KRAS p.G12C. Compound 50 also exhibited satisfactory selectivity, moderate pharmacokinetic characters, and good anticancer effects in vivo. Meaningfully, the identification of these compounds highlights the necessity of an appropriate conformational constraint for acquiring the applicable binding pose in the cryptic pocket of KRAS, and the results support efforts toward design of KRAS inhibitors with novel skeleton and binding mechanism could be beneficial for targeting the acquired drug resistance.

First description of males of Ensiferothrips wallacei Mound amp; Tree (Thripidae: Dendrothripinae) with variation in fore wing setae.

The genus Ensiferothrips now includes four described species, it is similar to Dendrothrips in the structure of the abdominal tergites and hind coxae, also the position of the fore wing cilia, but the wing apex bears a stout seta, and the costal setae are very stout. It was originally known from New Caledonia based on a single species, E. primus Bianchi, but subsequently E. secundus Mound was described from Lord Howe Island on Smilax australis [Smilacaceae](Mound 1999). More recently, Mound and Tree (2016) described two further species, E. lamingtoni from Queensland, Australia on Quintinia sieberi [Grossulariaceae] and E. wallacei from Indonesia without host plant information. A single specimen of the later species has also been recorded from Hainan, China (Zhang et al. 2018). The genus is clearly tropical in distribution, from south China to northern Australia, revealing the strong connection between south China, southeast Asia and northern Australia. Little biological information is known of these species, though they seem to live on hard mature leaves (Mound Tree 2020). In this study, a series of specimens of E. wallacei was found from Hainan on Smilax sp. The first description of the male of this species is presented here, together with interesting variation in the chaetotaxy of the fore wings.

Synthesis and evaluation of imidazo[1,2-a]pyrazine derivatives as small molecule Gαq/11 inhibitors against uveal melanoma.

Uveal melanoma (UM) is an aggressive malignancy with high mortality in adults and lacks effective systemic therapies. Activating gene mutations related to the Gαq/11 signaling pathway are prevalent in UM, and Gαq/11 inhibitors have shown anti-UM activity in vitro and in vivo. In this study, we designed and synthesized a series of imidazo[1,2-a]pyrazine derivatives as Gαq/11 inhibitors, and discovered GQ352 with the selective antiproliferative activity against UM cells. Importantly, GQ352 directly binds to the Gαq and inhibits the dissociation of Gαßγ heterotrimers with the IC50 value of 8.9 µM. GQ352 inhibits UM tumorigenesis by suppressing Gαq/11 downstream ERK phosphorylation and YAP dephosphorylation, as shown in Western blot analysis. In addition, GQ352 displayed reasonable physiochemical properties and human liver microsome stability, indicating the potential application in UM treatment.

Structure-based optimization of Toddacoumalone as highly potent and selective PDE4 inhibitors with anti-inflammatory effects.

Phosphodiesterase-4 (PDE4) is an important drug target for inflammatory diseases. Previously, we identified a series of novel PDE4 inhibitors derived from the natural Toddacoumalone, among which the hit compound 2 with a naphthyridine scaffold showed moderate potency with the IC50 value of 400 nM. Based on the co-crystal structure of PDE4D-2, further structural optimizations and structure-activity relationship studies led to a highly potent PDE4 inhibitor 23a with the IC50 value of 0.25 nM and excellent selectivity profiles over other PDEs (>4000-fold). The co-crystal structure of PDE4D-23a elucidated that 23a has strong interactions with the M and Q pocket of PDE4D. Importantly, compound 23a significantly inhibits the release of inflammatory cytokines TNF-α and IL-6 in lipopolysaccharide-stimulated RAW264.7 cells. Thus, compound 23a with a naphthyridine scaffold is a promising PDE4 inhibitor for the treatment of inflammatory diseases.

Discovery of small molecule Gαq/11 protein inhibitors against uveal melanoma.

Constitutively activated G proteins caused by specific mutations mediate the development of multiple malignancies. The mutated Gαq/11 are perceived as oncogenic drivers in the vast majority of uveal melanoma (UM) cases, making directly targeting Gαq/11 to be a promising strategy for combating UM. Herein, we report the optimization of imidazopiperazine derivatives as Gαq/11 inhibitors, and identified GQ262 with improved Gαq/11 inhibitory activity and drug-like properties. GQ262 efficiently blocked UM cell proliferation and migration in vitro. Analysis of the apoptosis-related proteins, extracellular signal-regulated kinase (ERK), and yes-associated protein (YAP) demonstrated that GQ262 distinctly induced UM cells apoptosis and disrupted the downstream effectors by targeting Gαq/11 directly. Significantly, GQ262 showed outstanding antitumor efficacy in vivo with good safety at the testing dose. Collectively, our findings along with the favorable pharmacokinetics of GQ262 revealed that directly targeting Gαq/11 may be an efficient strategy against uveal melanoma.

Discovery and Structural Optimization of Toddacoumalone Derivatives as Novel PDE4 Inhibitors for the Topical Treatment of Psoriasis.

Psoriasis is a common immune-mediated skin disorder manifesting in abnormal skin plaques, and phosphodiesterase 4 (PDE4) is an effective target for the treatment of inflammatory diseases such as psoriasis. Toddacoumalone is a natural PDE4 inhibitor with moderate potency and imperfect drug-like properties. To discover novel and potent PDE4 inhibitors with considerable druggability, a series of toddacoumalone derivatives were designed and synthesized, leading to the compound (2R,4S)-6-ethyl-2-(2-hydroxyethyl)-2,8-dimethyl-4-(2-methylprop-1-en-1-yl)-2,3,4,6-tetrahydro-5H-pyrano[3,2-c][1,8]naphthyridin-5-one (33a) with high inhibitory potency (IC50 = 3.1 nM), satisfactory selectivity, favorable skin permeability, and a well-characterized binding mechanism. Encouragingly, topical administration of 33a exhibited remarkable therapeutic effects in an imiquimod-induced psoriasis mouse model.

Targeting mutated GTPase KRAS in tumor therapies.

Kirsten rat sarcoma virus oncogene (KRAS) mutation accounts for approximately 85% of RAS-driven cancers, and participates in multiple signaling pathways and mediates cell proliferation, differentiation and metabolism. KRAS has been considered as an "undruggable" target due to the lack of effective direct inhibitors, although high frequency of KRAS mutations have been identified in multiple carcinomas in the past decades. Encouragingly, the KRASG12C inhibitor AMG510 (sotorasib), which has been approved for treating NSCLC and CRC recently, makes directly targeting KRAS the most promising strategy for cancer therapy. To better understand the current state of KRAS inhibitors, this review summarizes the biological functions of KRAS, the structure-activity relationship studies of the small-molecule inhibitors that directly target KRAS, and highlights the therapeutic agents with improved selectivity, bioavailability and physicochemical properties. Furthermore, the combined medication that can enhance efficacy and overcome drug resistance of KRAS covalent inhibitors is also reviewed.

Demethylative Alkylation of Methionine Residue by Employing the Sulfonium as the Key Intermediate.

Methionine (Met) offers a valuable handle to achieve peptide chemical modification owing to its unique thioether functional group. In contrast with cysteine, the site-selective functionalization of the hydrophobic and redox-sensitive thioether motif on peptides is still challenging, and strategies for diversification on the Met residue are rarely disclosed. Herein we report a transition-metal-free and redox-neutral approach for Met diversification with substrate diversity, which could be applied to synthesize cyclic peptides.

Design, Synthesis, and Evaluation of Small Molecule Gαq/11 Protein Inhibitors for the Treatment of Uveal Melanoma.

Uveal melanoma is the ocular malignancy and mainly driven by oncogenic mutations of Gαq/11 proteins. Previous targeted therapy for melanoma treatment was limited to specific downstream signaling pathway, and inhibiting the "molecular switches" G proteins for melanoma treatment therapy was rarely described. We herein report the discovery of imidazopiperazine derivatives as Gαq/11 protein inhibitors. The most promising compound GQ127 showed good efficacy and safety in inositol monophosphate (IP1) assay by directly inhibiting Gαq/11 proteins. GQ127 induced uveal melanoma cells apoptosis and displayed potent antitumor activities in uveal melanoma cells viability, migration, and invasion. The effects of GQ127 on Gαq/11 signaling pathway were confirmed by analyzing the downstream effectors yes-associated protein (YAP) and extracellular signal-regulated kinase (ERK). More importantly, GQ127 significantly suppressed UM xenograft growth in mouse model without severe toxicity at the testing dose. These findings provide a lead compound that directly targets the Gαq/11 proteins for uveal melanoma treatment.