Identification of a ligand-binding site on tubulin mediating the tubulin-RB3 interaction.

For decades, microtubules-composed of αβ-tubulin dimers-have been primary targets for cancer chemotherapy. While eight binding sites on the tubulin dimer have been structurally characterized, this study reveals a ninth. We found that the tubulin inhibitor Tumabulin-1 (TM1, a BML284 derivative) binds simultaneously to the well-known colchicine site and a previously unknown site, designated as Tumabulin site.

Efficacy and survival outcomes of alectinib vs. crizotinib in ALK‑positive NSCLC patients with CNS metastases: A retrospective study.

Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) have transformed the treatment paradigm for patients with ALK-positive non-small cell lung cancer (NSCLC). Yet the differential efficacy between alectinib and crizotinib in treating patients with NSCLC and central nervous system (CNS) metastases has been insufficiently studied. A retrospective analysis was conducted of clinical outcomes of patients with ALK-positive NSCLC and CNS metastases treated at the Shandong Cancer Centre.

Structure-based design and synthesis of BML284 derivatives: A novel class of colchicine-site noncovalent tubulin degradation agents.

Our previous studies have demonstrated that BML284 is a colchicine-site tubulin degradation agent. To improve its antiproliferative properties, 45 derivatives or analogs of BML284 were designed and synthesized based on the cocrystal structure of BML284 and tubulin. Among them, 5i was the most potent derivative, with IC values ranging from 0.

Fragment growth-based discovery of novel TNIK inhibitors for the treatment of colorectal cancer.

Traf2-and Nck-interacting protein kinase (TNIK) plays an important role in regulating signal transduction of the Wnt/β-catenin pathway and is considered an important target for the treatment of colorectal cancer. Inhibiting TNIK has potential to block abnormal Wnt/β-catenin signal transduction caused by colorectal cancer mutations. We discovered a series of 6-(1-methyl-1H-imidazole-5-yl) quinoline derivatives as TNIK inhibitors through Deep Fragment Growth and virtual screening.

Efficacy of immunotherapy in HER2-mutated non-small cell lung cancer: a single-arm meta-analysis.

Background: Non-small cell lung cancers (NSCLC) harboring Human Epidermal Growth Factor Receptor 2 (HER2) mutations represent a distinct subset with unique therapeutic challenges. Although immune checkpoint inhibitors (ICIs) have been transformative in lung cancer treatment, the efficacy of ICIs in HER2-mutated NSCLC remains to be established.

Methods: We systematically searched for real-world studies investigating the use of ICIs in treating HER2-mutated NSCLC, sourced from the PubMed, Cochrane Library, and Embase databases.

Discovery of 4-amino-1,6-dihydro-7H-pyrrolo[2,3-d]pyridazin-7-one derivatives as potential receptor-interacting serine/threonine-protein kinase 1 (RIPK1) inhibitors.

Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) is an important regulatory factor in the necroptosis signaling pathway, and is considered an attractive therapeutic target for treating multiple inflammatory diseases. Herein, we describe the design, synthesis, and structure-activity relationships of 4-amino-1,6-dihydro-7H-pyrrolo [2,3-d]pyridazin-7-one derivatives as RIPK1 inhibitors. Among them, 13c showed favorable RIPK1 kinase inhibition activity with an IC value of 59.

Discovery, Optimization, and Evaluation of Potent and Selective DNA-PK Inhibitors in Combination with Chemotherapy or Radiotherapy for the Treatment of Malignancies.

Given the multifaceted biological functions of DNA-PK encompassing DNA repair pathways and beyond, coupled with the susceptibility of DNA-PK-deficient cells to DNA-damaging agents, significant strides have been made in the pursuit of clinical potential for DNA-PK inhibitors as synergistic adjuncts to chemo- or radiotherapy. Nevertheless, although substantial progress has been made with the discovery of potent inhibitors of DNA-PK, the clinical trial landscape requires even more potent and selective molecules. This necessitates further endeavors to expand the repertoire of clinically accessible DNA-PK inhibitors for the ultimate benefit of patients.

Recent Progress on Microtubule Degradation Agents.

Targeted protein degradation (TPD) has emerged as the most promising approach for the specific knockdown of disease-associated proteins and is achieved by exploiting the cellular quality control machinery. TPD technologies are highly advantageous in overcoming drug resistance as they degrade the whole target protein. Microtubules play important roles in many cellular processes and are among the oldest and most well-established targets for tumor chemotherapy.

Discovery and Evaluation of 3-Quinoxalin Urea Derivatives as Potent, Selective, and Orally Available ATM Inhibitors Combined with Chemotherapy for the Treatment of Cancer via Goal-Oriented Molecule Generation and Virtual Screening.

ATM plays an important role in DNA damage response and is considered a potential target in cancer therapies. In this study, a goal-directed molecular generation approach based on ligand similarity and target specificity was applied to sample active molecules, and they were screened virtually to identify the theoretical lead compound , which was later shown to inhibit ATM adequately. However, there is a main concern about its poor metabolic stability .

Tumor-infiltrating lymphocytes predict efficacy of immunotherapy in advanced non-small cell lung cancer: a single-center retrospective cohort study.

Background/purpose: The current study aimed to investigate the correlation between tumor-infiltrating lymphocytes (TILs) and immunotherapy efficacy in patients with advanced non-small cell lung cancer (NSCLC).

Materials And Methods: Eighty-nine patients with advanced NSCLC who received immune checkpoint inhibitors (ICIs) monotherapy were retrospectively enrolled in this study. The density of TILs in paraffin-embedded pathological tissues taken before receiving ICIs was quantitatively analyzed by immunohistochemical staining.

A novel chromophore reaction-based pyrrolopyrrole aza-BODIPY fluorescent probe for HS detection and its application in food spoilage.

In this work, we developed an aggregation-induced emission enhancement (AIEE) active and NIR emissive pyrrolopyrrole aza-BODIPY (PPAB) polymer (P1) for HS detection for the first time. P1 showed obvious colorimetric change from green to yellow-green and ratiometric fluorescence "turn on" phenomenon with 167 nm blue-shift (from dark red to bright green). The sensing mechanism revealed a novel chromophore reaction between imine in PPAB core and HS was involved, leading to less conjugated product.

Design, synthesis and biological evaluation of purine-based derivatives as novel JAK2/BRD4(BD2) dual target inhibitors.

Based on the pharmacological synergy of JAK2 and BRD4 in the NF-κB pathway and positive therapeutic effect of combination of JAK2 and BRD4 inhibitors in treating MPN and inflammation. A series of unique 9H-purine-2,6-diamine derivatives that selectively inhibited Janus kinase 2 (JAK2) and BRD4(BD2) were designed, prepared, and evaluated for their in vitro and in vivo potency. Among them, compound 9j exhibited acceptable inhibitory activity with IC values of 13 and 22 nM for BD2 of BRD4 and JAK2, respectively.

Hepatocyte phosphatase DUSP22 mitigates NASH-HCC progression by targeting FAK.

Nonalcoholic steatohepatitis (NASH), a common clinical disease, is becoming a leading cause of hepatocellular carcinoma (HCC). Dual specificity phosphatase 22 (DUSP22, also known as JKAP or JSP-1) expressed in numerous tissues plays essential biological functions in immune responses and tumor growth. However, the effects of DUSP22 on NASH still remain unknown.

Discovery, Optimization, and Evaluation of Potent and Selective PI3Kδ-γ Dual Inhibitors for the Treatment of B-cell Malignancies.

Nowadays, PI3Kδ-γ dual inhibitors have been approved for the treatment of B-cell malignancies. Dual inhibition of PI3Kδ and PI3Kγ represents a unique therapeutic opportunity and may confer greater benefits than either isoform inhibition alone in the management of hematological malignancies. However, currently available dual inhibitors of PI3Kδ-γ compromise in at least one of several essential properties in terms of potency, selectivity, and pharmacokinetic (PK) profiles.

Discovery of Potent and Selective Receptor-Interacting Serine/Threonine Protein Kinase 2 (RIPK2) Inhibitors for the Treatment of Inflammatory Bowel Diseases (IBDs).

Receptor-interacting serine/threonine protein kinase 2 (RIPK2) has been demonstrated to be a promising target for treating inflammatory diseases. Herein, we describe the discovery and optimization of a series of RIPK2 inhibitors derived from an FLT3 inhibitor, CHMFL-FLT3-165. Compound was identified to possess an IC value of 0.

Tripartite motif-containing protein 31 confers protection against nonalcoholic steatohepatitis by deactivating mitogen-activated protein kinase kinase kinase 7.

Background Aims: As a global health threat, NASH has been confirmed to be a chronic progressive liver disease that is strongly associated with obesity. However, no approved drugs or efficient therapeutic strategies are valid, mainly because its complicated pathological processes is underestimated.

Approach Results: We identified the RING-type E3 ubiquitin transferase-tripartite motif-containing protein 31 (TRIM31), a member of the E3 ubiquitin ligases family, as an efficient endogenous inhibitor of transforming growth factor-beta-activated kinase 1 (mitogen-activated protein kinase kinase kinase 7; MAP3K7), and we further confirmed that TRIM31 is an MAP3K7-interacting protein and promotes MAP3K7 degradation by enhancing ubiquitination of K48 linkage in hepatocytes.

The E3 ubiquitin-protein ligase Trim31 alleviates non-alcoholic fatty liver disease by targeting Rhbdf2 in mouse hepatocytes.

Systemic metabolic syndrome significantly increases the risk of morbidity and mortality in patients with non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). However, no effective therapeutic strategies are available, practically because our understanding of its complicated pathogenesis is poor. Here we identify the tripartite motif-containing protein 31 (Trim31) as an endogenous inhibitor of rhomboid 5 homolog 2 (Rhbdf2), and we further determine that Trim31 directly binds to Rhbdf2 and facilitates its proteasomal degradation.

Synthesis and biological evaluation of 6-(pyrimidin-4-yl)-1H-pyrazolo[4,3-b]pyridine derivatives as novel dual FLT3/CDK4 inhibitors.

FMS-like tyrosine kinase-3 (FLT3) and cyclin-dependent kinase 4/6 (CDK4/6) inhibitors have been proven to play a significant role in tumor therapy. Herein, based on the previously reported JAK2/FLT3 inhibitor 18e, we described the synthesis, structure-activity relationship and biological evaluation of a series of unique 6-(pyrimidin-4-yl)-1H-pyrazolo[4,3-b]pyridine derivatives that inhibited FLT3 and CDK4 kinases. The optimized compound 23k exhibited low nanomolar range activities with IC values of 11 and 7 nM for FLT3 and CDK4, respectively.

Structure-Based Design and Synthesis of N-Substituted 3-Amino-β-Carboline Derivatives as Potent αβ-Tubulin Degradation Agents.

So far, relatively few small molecules have been reported to promote tubulin degradation. Our previous studies have found that compound , a noncovalent colchicine-site ligand, was capable of promoting αβ-tubulin degradation. To further improve its antiproliferative activity, 66 derivatives or analogues of were designed and synthesized based on -tubulin cocrystal structure.

Development of a novel chromophore reaction-based fluorescent probe for biogenic amines detection.

Biogenic amines (BAs) are important biomarkers to monitor meat spoilage. However, the design of efficient BA fluorescent probes with distinct colorimetric and ratiometric fluorescent dual-channels is still a critical challenge because of similar chemical properties and basicity between BAs and other amines. Herein, pyrrolopyrrole cyanine (PPCy-1) is reported to display distinctly high reactivity toward BAs through an ultrasensitive irreversible chromophore reaction for the first time.

Immune checkpoint inhibitors plus anlotinib versus anlotinib alone as third-line treatment in advanced non-small-cell lung cancer: a retrospective study.

This study was conducted to evaluate the efficacy of immune checkpoint inhibitors (ICIs) plus anlotinib versus anlotinib alone to provide guidance for clinical treatment of non-small-cell lung cancer. The records of 139 patients with advanced non-small-cell lung cancer who received at least one dose of ICIs plus anlotinib (IA group) or single-agent anlotinib (AA group) were retrospectively reviewed. The efficacy of the treatments, survival outcomes and adverse events were analyzed.

Discovery, Optimization, and Evaluation of Quinazolinone Derivatives with Novel Linkers as Orally Efficacious Phosphoinositide-3-Kinase Delta Inhibitors for Treatment of Inflammatory Diseases.

Guided by molecular docking, a commonly used open-chain linker was cyclized into a five-membered pyrrolidine to lock the overall conformation of the propeller-shaped molecule. Different substituents were introduced into the pyrrolidine moiety to block oxidative metabolism. Surprisingly, it was found that a small methyl substituent could be used to alleviate the oxidative metabolism of pyrrolidine while maintaining or enhancing potency, which could be described as a "magic methyl".

Commensal microbiota contributes to predicting the response to immune checkpoint inhibitors in non-small-cell lung cancer patients.

Immunotherapy against cancer, through immune checkpoint inhibitors targeting the programmed cell death-1/programmed cell death-ligand 1 axis, is particularly successful in tumors by relieving the immune escape. However, interindividual responses to immunotherapy are often heterogeneous. Therefore, it is essential to screen out predictive tumor biomarkers.

Discovery of 3-(4-(2-((1-Indol-5-yl)amino)-5-fluoropyrimidin-4-yl)-1-pyrazol-1-yl)propanenitrile Derivatives as Selective TYK2 Inhibitors for the Treatment of Inflammatory Bowel Disease.

TYK2 mediates signaling of IL-23, IL-12, and Type I IFN-driven responses that are critical in immune-mediated diseases. Herein, we report the design, synthesis, and structure-activity relationships (SARs) of 3-(4-(2-((1-indol-5-yl)amino)-5-fluoropyrimidin-4-yl)-1-pyrazol-1-yl)propanenitrile derivatives as selective TYK2 inhibitors. Among them, compound exhibited acceptable TYK2 inhibition with an IC value of 9 nM, showed satisfactory selectivity characteristics over the other three homologous JAK kinases, and performed good functional potency in the JAK/STAT signaling pathway on lymphocyte lines and human whole blood.