Real-World Data on the Effectiveness and Safety of Filgotinib for Ulcerative Colitis in Japanese Patients: A Single-Center Experience.

Introduction Filgotinib is a JAK-1 selective inhibitor approved for ulcerative colitis (UC) treatment in Japan. Its effectiveness has been confirmed but remains unknown in actual clinical practice. Therefore, we aimed to evaluate the effectiveness and safety of filgotinib and identify suitable patients in the Japanese population. Methods We retrospectively reviewed the background, clinical course, and laboratory data of patients treated with filgotinib 200 mg for UC between May 2022 and December 2023. Results The median observation period for the 25 patients was 232 days (interquartile ranges (IQR) 102-405). The median age of the patients was 43 years (IQR 29-55), disease duration was nine years (IQR 2-12), and 36% (9/25) of patients were biologic or small molecule naïve. The median patient-reported outcome (PRO2) and partial Mayo (pMayo) scores at agent initiation were 3 (IQR 1-4) and 4.5 (IQR 3-6), respectively. The PRO2 and pMayo scores improved significantly two weeks after treatment initiation (p < 0.05). Clinical remission rates at 24 weeks after treatment initiation were 60% (15/25) for PRO2 ≤ 1 and 52% (13/25) for pMayo ≤ 1. The Mayo endoscopic subscore significantly improved after filgotinib initiation (p=0.04), and the endoscopic remission rate was 47% (8/17). At 24 weeks, patients in clinical remission, compared to those not in remission, had significantly lower baseline PRO2 and pMayo scores and longer disease duration (p=0.03, p=0.03, and p=0.04, respectively). The filgotinib persistence rate was 68% (17/25), with no discontinuation because of adverse events. Patients who continued treatment had significantly lower PRO2, pMayo scores, and blood neutrophil counts at initiation than those who discontinued (p=0.02, p=0.03, and p=0.02, respectively). Conclusion Filgotinib appears to be effective and safe in Japanese patients with UC. Effectiveness and persistence were high in patients whose PRO2 and pMayo scores were low at the time of treatment initiation.

Trifluoromethylation Enables Compact 2D Linear Stacking and Improves the Efficiency and Stability of Q-PHJ Organic Solar Cells.

Compared to the bulk heterojunction (BHJ) devices, the quasiplanar heterojunction (Q-PHJ) exhibits a more stable morphology and superior charge transfer performance. To achieve both high efficiency and long-term stability, it is necessary to design new materials for Q-PHJ devices. In this study, QxIC-CF3 and QxIC-CH3 are designed and synthesized for the first time. The trifluoromethylation of the central core exerts a modulatory effect on the molecular stacking pattern, leveraging the strong electrostatic potential and intermolecular interactions. Compared with QxIC-CH3, the single crystal structure reveals that QxIC-CF3 exhibits a more compact 2D linear stacking behavior. These benefits, combined with the separated electron and hole transport channels in Q-PHJ device, lead to increased charge mobility and reduced energy loss. The devices based on D18/QxIC-CF3 exhibit an efficiency of 18.1%, which is the highest power conversion efficiency (PCE) for Q-PHJ to date. Additionally, the thermodynamic stability of the active layer morphology enhances the lifespan of the aforementioned devices under illumination conditions. Specifically, the T80 is 420 h, which is nearly twice that of the renowned Y6-based BHJ device (T80 = 220 h). By combining the advantages of the trifluoromethylation and Q-PHJ device, efficient and stable organic solar cell devices can be constructed.

Insights into the structural and functional activities of forgotten Kinases: PCTAIREs CDKs.

In cells, signal transduction heavily relies on the intricate regulation of protein kinases, which provide the fundamental framework for modulating most signaling pathways. Dysregulation of kinase activity has been implicated in numerous pathological conditions, particularly in cancer. The druggable nature of most kinases positions them into a focal point during the process of drug development. However, a significant challenge persists, as the role and biological function of nearly one third of human kinases remains largely unknown.Within this diverse landscape, cyclin-dependent kinases (CDKs) emerge as an intriguing molecular subgroup. In human, this kinase family encompasses 21 members, involved in several key biological processes. Remarkably, 13 of these CDKs belong to the category of understudied kinases, and only 5 having undergone broad investigation to date. This knowledge gap underscores the pressing need to delve into the study of these kinases, starting with a comprehensive review of the less-explored ones.Here, we will focus on the PCTAIRE subfamily of CDKs, which includes CDK16, CDK17, and CDK18, arguably among the most understudied CDKs members. To contextualize PCTAIREs within the spectrum of human pathophysiology, we conducted an exhaustive review of the existing literature and examined available databases. This approach resulted in an articulate depiction of these PCTAIREs, encompassing their expression patterns, 3D configurations, mechanisms of activation, and potential functions in normal tissues and in cancer.We propose that this effort offers the possibility of identifying promising areas of future research that extend from basic research to potential clinical and therapeutic applications.

A small molecule compound targeting hemagglutinin inhibits influenza A virus and exhibits broad-spectrum antiviral activity.

Influenza A virus (IAV) is a widespread pathogen that poses a significant threat to human health, causing pandemics with high mortality and pathogenicity. Given the emergence of increasingly drug-resistant strains of IAV, currently available antiviral drugs have been reported to be inadequate to meet clinical demands. Therefore, continuous exploration of safe, effective and broad-spectrum antiviral medications is urgently required. Here, we found that the small molecule compound J1 exhibited low toxicity both in vitro and in vivo. Moreover, J1 exhibits broad-spectrum antiviral activity against enveloped viruses, including IAV, respiratory syncytial virus (RSV), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), human coronavirus OC43 (HCoV-OC43), herpes simplex virus type 1 (HSV-1) and HSV-2. In this study, we explored the inhibitory effects and mechanism of action of J1 on IAV in vivo and in vitro. The results showed that J1 inhibited infection by IAV strains, including H1N1, H7N9, H5N1 and H3N2, as well as by oseltamivir-resistant strains. Mechanistic studies have shown that J1 blocks IAV infection mainly through specific interactions with the influenza virus hemagglutinin HA2 subunit, thereby blocking membrane fusion. BALB/c mice were used to establish a model of acute lung injury (ALI) induced by IAV. Treatment with J1 increased survival rates and reduced viral titers, lung index and lung inflammatory damage in virus-infected mice. In conclusion, J1 possesses significant anti-IAV effects in vitro and in vivo, providing insights into the development of broad-spectrum antivirals against future pandemics.

Small molecule agents against alopecia: Potential targets and related pathways.

Alopecia has emerged as a global concern, extending beyond the middle-aged and elderly population and increasingly affecting younger individuals. Despite its growing prevalence, the treatment options and effective drugs for alopecia remain limited due to the incomplete understanding of its underlying mechanisms. Therefore, it is urgent to explore the pathogenesis of alopecia and discover novel and safer therapeutic agents. This review provided an overview of the prevailing clinical disorders of alopecia, and the key pathways and targets involved in hair growth process. Additionally, it discusses FDA-approved drugs and clinical candidates for the treatment of alopecia, and explores small molecule compounds with anti-alopecia potential in the drug discovery phase. These endeavors are expected to provide researchers with valuable scientific insights and practical information for anti-alopecia drug discovery.

A simulation-guided approach to the selection of RPLC columns for platform small molecule separations.

Simulations were conducted to evaluate the potential of several hundred reversed-phase columns to separate small molecules. By calculating the retention factor of compounds in randomly generated virtual mixtures via the HSM (hydrophobic subtraction model) and applying basic chromatography theory, the simulation can estimate the retention time and peak width of every virtual compound and calculate the resolution between every adjacent pair of compounds. A preferred column set based on the number of successful separations of randomly generated virtual mixtures was developed. The tandem-column liquid chromatography (TC-LC) approach can separate 53.2 % of the 16-compound samples using 20 tandem-column pairs, while a single-column approach can only separate 42.6 % of the 16-compound samples with 20 single columns. The preferred set of columns obtained from the simulation was almost the same as the empirical set of columns previously obtained. In screening applications, TC-LC can achieve a comparably successful separation factor (selectivity) with a smaller column inventory (nine 50-mm columns) compared to the larger inventory needed by single-column LC (twenty-one 100-mm columns).

Design, synthesis, pharmacological evaluation, and computational study of benzo[d] isothiazol-based small molecule inhibitors targeting PD-1/PD-l1 interaction.

Blockade of the programmed cell death-1 (PD-1)/programmed cell death ligand 1 (PD-L1) pathway is an attractive strategy for immunotherapy, but the clinical application of small molecule PD-1/PD-L1 inhibitors remains unclear. In this work, based on BMS-202 and our previous work YLW-106, a series of compounds with benzo[d]isothiazol structure as scaffold were designed and synthesized. Their inhibitory activity against PD-1/PD-L1 interaction was evaluated by a homogeneous time-resolved fluorescence (HTRF) assay. Among them, LLW-018 (27c) exhibited the most potent inhibitory activity with an IC50 value of 2.61 nM. The cellular level assays demonstrated that LLW-018 exhibited low cytotoxicity against Jurkat T and MDA-MB-231. Further cell-based PD-1/PD-L1 blockade bioassays based on PD-1 NFAT-Luc Jurkat cells and PD-L1 TCR Activator CHO cells indicated that LLW-018 could interrupt PD-1/PD-L1 interaction with an IC50 value of 0.88 µM. Multi-computational methods, including molecular docking, molecular dynamics, MM/GBSA, MM/PBSA, Metadynamics, and QM/MM MD were utilized on PD-L1 dimer complexes, which revealed the binding modes and dissociation process of LLW-018 and C2-symmetric small molecule inhibitor LCH1307. These results suggested that LLW-018 exhibited promising potency as a PD-1/PD-L1 inhibitor for further investigation.

MAGPIE: An interactive tool for visualizing and analyzing protein-ligand interactions.

Quantitative tools to compile and analyze biomolecular interactions among chemically diverse binding partners would improve therapeutic design and aid in studying molecular evolution. Here we present Mapping Areas of Genetic Parsimony In Epitopes (MAGPIE), a publicly available software package for simultaneously visualizing and analyzing thousands of interactions between a single protein or small molecule ligand (the "target") and all of its protein binding partners ("binders"). MAGPIE generates an interactive three-dimensional visualization from a set of protein complex structures that share the target ligand, as well as sequence logo-style amino acid frequency graphs that show all the amino acids from the set of protein binders that interact with user-defined target ligand positions or chemical groups. MAGPIE highlights all the salt bridge and hydrogen bond interactions made by the target in the visualization and as separate amino acid frequency graphs. Finally, MAGPIE collates the most common target-binder interactions as a list of "hotspots," which can be used to analyze trends or guide the de novo design of protein binders. As an example of the utility of the program, we used MAGPIE to probe how different antibody fragments bind a viral antigen; how a common metabolite binds diverse protein partners; and how two ligands bind orthologs of a well-conserved glycolytic enzyme for a detailed understanding of evolutionarily conserved interactions involved in its activation and inhibition. MAGPIE is implemented in Python 3 and freely available at https://github.com/glasgowlab/MAGPIE, along with sample datasets, usage examples, and helper scripts to prepare input structures.

STING-Activating Small Molecular Therapeutics for Cancer Immunotherapy.

Immuno-oncology has become a revolutionary strategy for cancer treatment. Therapeutic interventions based on adaptive immunity through immune checkpoint therapy or chimeric antigen receptor T cells have received clinical approval for monotherapy and combination treatment use in various cancers. Although these treatments have achieved clinical successes, only a minority of cancer patients show a response, highlighting the urgent need to discover new therapeutic molecules that could be exploited to improve clinical outcomes and pave the way for the next generation of immunotherapy. Given the critical role of the innate immune system against infection and cancer, substantial efforts have been dedicated to developing novel anticancer therapeutics that target these pathways. Targeting the stimulator of interferon genes (STING) pathway is a powerful strategy to generate durable antitumor response, and activation of the adaptor protein STING induces the initiation of transcriptional cascades, thereby producing type I interferons, pro-inflammatory cytokines and chemokines. Various STING agonists, including natural or synthetic cyclic dinucleotides (CDNs) have been developed as anticancer therapeutics. However, since most CDNs are confined to intratumoral administration, there has been a great interest in developing non-nucleotide agonists for systemic treatment. Here we review the current development of STING-activating therapeutics in both preclinical or clinical stages.

MYB as a Critical Transcription Factor and Potential Therapeutic Target in AML.

Myb was identified over four decades ago as the transforming component of acute leukemia viruses in chickens. Since then it has become increasingly apparent that dysregulated MYB activity characterizes many blood cancers, including acute myeloid leukemia, and that it represents the most "addictive" oncoprotein in many, if not all, such diseases. As a consequence of this tumor-specific dependency for MYB, it has become a major focus of efforts to develop specific antileukemia drugs. Much attention is being given to ways to interrupt the interaction between MYB and cooperating factors, in particular EP300/KAT3B and CBP/KAT3A. Aside from candidates identified through screening of small molecules, the most exciting prospect for novel drugs seems to be the design of peptide mimetics that interfere directly at the interface between MYB and its cofactors. Such peptides combine a high degree of target specificity with good efficacy including minimal effects on normal hematopoietic cells.

Assessing the Survival of Human Plasma Cells Ex Vivo.

One way memory B cells provide protection is by rapidly differentiating into plasma cells. Plasma cells are vital in providing long-term protection against pathogens; however, they can also be detrimental to health in the case of antibody-mediated autoimmunity. Therefore, compounds which modulate the survival of plasma cells have been of interest for therapeutic intervention. Investigation of ex vivo plasma cell survival has previously been limited by the low frequency of plasma cells in the blood. Here we describe a novel ex vivo culture system that only requires 3000-5000 cells per condition. This method permits the assessment of human plasma cell survival derived from blood and can assess the impact of small molecule inhibitors on plasma cell viability.

Synthetic routes and clinical application of Small-Molecule HER2 inhibitors for cancer therapy.

This comprehensive review undertakes a meticulous scrutiny of the synthesis and clinical applications pertaining to small-molecule tyrosine kinase inhibitors (TKIs) directed towards the human epidermal growth factor receptor 2 (HER2), a pivotal protagonist in the pathogenesis of cancer. Focused on compounds like lapatinib, neratinib, and tucatinib, the review delves into the intricate synthesis strategies, emphasizing the challenges associated with their structural complexity. The clinical utilization of HER2 TKIs underscores noteworthy strides in the therapeutic landscape for HER2-positive breast and gastric malignancies. Lapatinib, a dual HER2/ epidermal growth factor receptor (EGFR) inhibitor, has demonstrated efficacy in combination therapies, addressing the need for overcoming resistance mechanisms. Neratinib, an irreversible HER2 inhibitor, presents a promising avenue for patients with refractory tumors. Tucatinib, strategically engineered to traverse the blood-brain barrier, epitomizes a groundbreaking advancement in the management of metastatic HER2-positive breast cancer manifesting cerebral involvement. Despite their success, challenges such as resistance mechanisms and off-target effects persist, urging continuous research for the development of next-generation HER2 TKIs. This comprehensive review serves as a valuable resource for pharmaceutical scientists, offering insights into the synthetic intricacies and clinical impact of small-molecule TKIs targeting HER2.

BTK inhibitors: past, present, and future.

Bruton's tyrosine kinase (BTK) inhibitors have revolutionized the treatment landscape for B cell lymphomas such as chronic lymphocytic leukemia (CLL). The first-in-class BTK inhibitor ibrutinib has recently been succeeded by covalent BTK inhibitors that are safer but still face challenges of resistance mutations. The noncovalent BTK inhibitor pirtobrutinib was recently approved for relapsed and refractory CLL, and whether noncovalent BTK inhibitors will supplant covalent BTK inhibitors as upfront treatment options either alone or in combination will be determined. Meanwhile, newer BTK inhibitors and BTK degraders are vying for their place in the potential future landscape of B cell cancers as well as autoimmune diseases. This review will cover the latest progress in BTK inhibitor development and where the field is moving in light of these recent discoveries.

N-methylmorpholine incorporation into the structure of biphenyl leads to the bioactive inhibitor of PD-1/PD-L1 interaction.

We present new small-molecular probes targeting the human PD-L1 protein. The molecules were designed by incorporating a newly discovered N-methylmorpholine substituent into a known biphenyl-based structure. Four prototype derivatives of 4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-carbonitrile (STD4), comprising a morpholine substituent fused with a biphenyl core at different orientations were first verified for their potential binding to PD-L1 using the molecular docking method. A more favorable 7-phenyl derivative of STD4 was then equipped with an amide bond, pyridine, and either a tris(hydroxymethyl)aminomethane or serinol tail leading to two final molecules. Among them, compound 1c showed activity in three bioassays, i.e., the homogenous time-resolved fluorescence (HTRF) assay, immune checkpoint blockade (ICB) assay, and T-cell activation (TCA) assay. Our work shows that morpholine can substitute for dioxane and becomes a promising component in PD-L1-targeting molecules. This finding unlocks new avenues for optimizing PD-L1-targeting compounds, presenting exciting prospects for future developments in this field.

Versatile function of NF-ĸB in inflammation and cancer.

Nuclear factor-kappaB (NF-ĸB) plays a crucial role in both innate and adaptive immune systems, significantly influencing various physiological processes such as cell proliferation, migration, differentiation, survival, and stemness. The function of NF-ĸB in cancer progression and response to chemotherapy has gained increasing attention. This review highlights the role of NF-ĸB in inflammation control, biological mechanisms, and therapeutic implications in cancer treatment. NF-ĸB is instrumental in altering the release of inflammatory factors such as TNF-α, IL-6, and IL-1ß, which are key in the regulation of carcinogenesis. Specifically, in conditions including colitis, NF-ĸB upregulation can intensify inflammation, potentially leading to the development of colorectal cancer. Its pivotal role extends to regulating the tumor microenvironment, impacting components such as macrophages, fibroblasts, T cells, and natural killer cells. This regulation influences tumorigenesis and can dampen anti-tumor immune responses. Additionally, NF-ĸB modulates cell death mechanisms, notably by inhibiting apoptosis and ferroptosis. It also has a dual role in stimulating or suppressing autophagy in various cancers. Beyond these functions, NF-ĸB plays a role in controlling cancer stem cells, fostering angiogenesis, increasing metastatic potential through EMT induction, and reducing tumor cell sensitivity to chemotherapy and radiotherapy. Given its oncogenic capabilities, research has focused on natural products and small molecule compounds that can suppress NF-ĸB, offering promising avenues for cancer therapy.

Development and Evaluation of an Expedited System for Creation of Single Walled Carbon Nanotube Platforms.

Single-walled carbon nanotubes (SWNT) have a strong and stable near-infrared (nIR) fluorescence that can be used to selectively detect target analytes, even at the single molecule level, through changes in either their fluorescence intensity or emission peak wavelength. SWNTs have been employed as NIR optical sensors for detecting a variety of analytes. However, high costs, long fabrication times, and poor distributions limit the current methods for immobilizing SWNT sensors on solid substrates. Recently, our group reported a protocol for SWNT immobilization with high fluorescence yield, longevity, fluorescence distribution, and sensor response, unfortunately this process takes 5 days to complete. Herein we report an improved method to immobilize SWNT sensors that only takes 2 days and results in higher fluorescence intensity while maintaining a high level of SWNT distribution. We performed surface morphology and chemical composition tests on the original and new synthesis methods and compared the sensor response rates. The development of this new method of attaching SWNT sensors to a platform allows for creation of a sensing system in just 2 days without sacrificing the advantageous characteristics of the original, 5-day platforms.

Progress in Non-Fullerene Acceptors: Evolution from Small to Giant Molecules.

With the rapid development of non-fullerene acceptors (NFAs), the power conversion efficiency (PCE) of organic solar cells (OSCs) is increasing. According to their different chemical structures, NFAs can initially be divided into two categories: small molecule acceptors (SMAs) and polymerized small molecule acceptors (PSMAs). Due to the strong absorption capacity and controllable energy levels, the PCE of devices based on SMAs has approached 20%. Compared with SMAs, PSMAs have advantages in stability and flexibility, and the PCE of PSMA-based devices has exceeded 18%. However, the higher synthesis cost and lower batch repeatability hinder its further development. Recently, the concept of giant molecule acceptors (GMAs) has been proposed. These materials have a clear molecular structure and are considered novel acceptor materials that combine the advantages of SMAs and PSMAs. Currently, the PCE of devices based on GMAs has exceeded 19%. In this review, we will introduce the latest developments in SMAs, PSMAs, and GMAs. Then, the advantages of GMAs and the relationship between their structure and performance will be analyzed. In the end, perspectives on the opportunities and challenges of these materials are provided, which could inspire further development of NFAs for advanced OSCs.

Design and Performance of Small-Molecule Donors with Donor-π-Acceptor Architecture Toward Vacuum-Deposited Organic Photovoltaics Having Heretofore Highest Short-Circuit Current Density.

The development of high-performance organic photovoltaic materials is of crucial importance for the commercialization of organic solar cells (OSCs). Herein, two structurally simple donor-π-conjugated linker-acceptor (D-π-A)-configured small-molecule donors with methyl-substituted triphenylamine as D unit, 1,1-dicyanomethylene-3-indanone as A unit, and thiophene or furan as π-conjugated linker, named DTICPT and DTICPF, are developed. DTICPT and DTICPF are facilely prepared via a two-step synthetic process with simple procedures. DTICPF with a furan π-conjugated linker exhibits stronger and broader optical absorption, deeper highest occupied molecular orbital (HOMO) energy levels, and better charge transport, compared to its thiophene analog DTICPT. As a result, vacuum-deposited OSCs based on DTICPF: C70 show an impressive power conversion efficiency (PCE) of 9.36% (certified 9.15%) with short-circuit current density (Jsc) up to 17.49 mA cm-2 (certified 17.56 mA cm-2), which is the highest Jsc reported so far for vacuum-deposited OSCs. Besides, devices based on DTICPT: C70 and DTICPF: C70 exhibit excellent long-term stability under different aging conditions. This work offers important insights into the rational design of D-π-A configured small-molecule donors for high efficient and stable vacuum-deposited OSCs.

Design, synthesis, and evaluation of antitumor activity of 2-arylmethoxy-4-(2-fluoromethyl-biphenyl-3-ylmethoxy) benzylamine derivatives as PD-1/PD-l1 inhibitors.

A series of novel 2-arylmethoxy-4-(2-fluoromethyl-biphenyl-3-ylmethoxy) benzylamine derivatives was designed, synthesized, and evaluated for their antitumor effects as PD-1/PD-L1 inhibitors both in vitro and in vivo. Firstly, the ability of these compounds to block the PD-1/PD-L1 immune checkpoint was assessed using the homogeneous time-resolved fluorescence (HTRF) assay. Two of the compounds can strongly block the PD-1/PD-L1 interaction, with IC50 values of less than 10 nM, notably, compound HD10 exhibited significant clinical potential by inhibiting the PD-1/PD-L1 interaction with an IC50 value of 3.1 nM. Further microscale thermophoresis (MST) analysis demonstrated that HD10 had strong interaction with PD-L1 protein. Co-crystal structure (2.7 Å) analysis of HD10 in complex with the PD-L1 protein revealed a strong affinity between the compound and the target PD-L1 dimer. This provides a solid theoretical basis for further in vitro and in vivo studies. Next, a typical cell-based experiment demonstrated that HD10 could remarkably prevent the interaction of hPD-1 293 T cells from human recombinant PD-L1 protein, effectively restoring T cell function, and promoting IFN-γ secretion in a dose-dependent manner. Moreover, HD10 was effective in suppressing tumor growth (TGI = 57.31 %) in a PD-1/PD-L1 humanized mouse model without obvious toxicity. Flow cytometry, qPCR, and immunohistochemistry data suggested that HD10 inhibits tumor growth by activating the immune system in vivo. Based on these results, it seems likely that HD10 is a promising clinical candidate that should be further investigated.