TFF3 drives Hippo dependent EGFR-TKI resistance in lung adenocarcinoma.

Intrinsic and acquired resistance represent major obstacles to optimize outcomes in epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) targeted therapy in lung adenocarcinoma (LUAD). Hence, a deeper understanding of EGFR-TKI resistance mechanisms in LUAD will potentially assist in formulating strategies to delay or overcome such resistance. Herein, it was observed that trefoil factor 3 (TFF3) is a crucial mediator of the LUAD EGFR-TKI response.

Emerging insights into epigenetics and hematopoietic stem cell trafficking in age-related hematological malignancies.

Background: Hematopoiesis within the bone marrow (BM) is a complex and tightly regulated process predominantly influenced by immune factors. Aging, diabetes, and obesity are significant contributors to BM niche damage, which can alter hematopoiesis and lead to the development of clonal hematopoiesis of intermediate potential (CHIP). Genetic/epigenetic alterations during aging could influence BM niche reorganization for hematopoiesis or clonal hematopoiesis.

Isoxazole based nucleosides induce autophagy through the production of ROS and the suppression of the β-catenin pathway in human colorectal carcinoma cells.

β-catenin is frequently implicated in signaling pathways that regulate autophagy, and the production of reactive oxygen species (ROS) has been linked to autophagy activation. Isoxazole-based nucleoside compounds have demonstrated anti-cancer properties. In this study, we report the identification of novel isoxazole-nucleosides as anti-tumor agents and their impact on autophagy in human colorectal carcinoma (CRC) cells.

Pyrimidine-triazole-tethered tert-butyl-piperazine-carboxylate suppresses breast cancer by targeting estrogen receptor signaling and β-catenin activation.

Several chemotherapeutics against breast cancer are constrained by their adverse effects and chemoresistance. The development of novel chemotherapeutics to target metastatic breast cancer can bring effective clinical outcomes. Many breast cancer patients present with tumors that are positive for estrogen receptors (ERs), highlighting the importance of targeting the ER pathway in this particular subtype.

Thiouracil and triazole conjugate induces autophagy through the downregulation of Wnt/β-catenin signaling pathway in human breast cancer cells.

Autophagy is vital for maintaining cellular homeostasis by breaking down unnecessary organelles and proteins within cells. Its activity varies abnormally in several diseases, including cancer, making it a potential target for therapeutic strategies. The Wnt/β-catenin signaling pathway significantly impacts cancer by stabilizing β-catenin protein and promoting the transcription of its target genes.

Combining Mitomycin C with inhibition of BAD phosphorylation enhances apoptotic cell death in advanced cervical cancer.

Objective: Mitomycin C (MMC), a DNA-damaging chemotherapeutic, is commonly used clinically for recurrent cervical carcinoma (CC), either alone or in combination. MMC generates DNA damage resulting in CC cell death yet also induces increased AKT-BAD phosphorylation associated with drug resistance and reduced clinical benefit. The present study evaluates the efficacy of combined MMC and a BAD phosphorylation inhibitor in CC.

Oxazine drug-seed induces paraptosis and apoptosis through reactive oxygen species/JNK pathway in human breast cancer cells.

Small molecule-driven JNK activation has been found to induce apoptosis and paraptosis in cancer cells. Herein pharmacological effects of synthetic oxazine (4aS, 7aS)-3-((4-(4‑chloro-2-fluorophenyl)piperazin-1-yl)methyl)-4-phenyl-4, 4a, 5, 6, 7, 7a-hexahydrocyclopenta[e] [1,2]oxazine (FPPO; BSO-07) on JNK-driven apoptosis and paraptosis has been demonstrated in human breast cancer (BC) MDA-MB231 and MCF-7 cells respectively. BSO-07 imparted significant cytotoxicity in BC cells, induced activation of JNK, and increased intracellular reactive oxygen species (ROS) levels.

Discovery of oxazine-linked pyrimidine as an inhibitor of breast cancer growth and metastasis by abrogating NF-κB activation.

Introduction: Nuclear factor kappa (NF-κB) plays a key role in cancer cell proliferation; thus, small molecule inhibitors of NF-κB activity can effectively inhibit breast cancer (BC) progression. We have previously reported oxazine and piperazine-linked pyrimidines as novel anti-cancer agents that can suppress NF-κB activation in BC cells. Moreover, the TRX-01 compound, an oxazine-linked pyrimidine, inhibited MCF-7 cells at a concentration of 9.

A novel drug prejudice scaffold-imidazopyridine-conjugate can promote cell death in a colorectal cancer model by binding to β-catenin and suppressing the Wnt signaling pathway.

Introduction: Globally, colorectal cancer (CRC) is the third most common type of cancer, and its treatment frequently includes the utilization of drugs based on antibodies and small molecules. The development of CRC has been linked to various signaling pathways, with the Wnt/β-catenin pathway identified as a key target for intervention.

Objectives: We have explored the impact of imidazopyridine-tethered chalcone-C (CHL-C) in CRC models.

Role of Neurotransmitters in Steady State Hematopoiesis, Aging, and Leukemia.

Haematopoiesis within the bone marrow (BM) represents a complex and dynamic process intricately regulated by neural signaling pathways. This delicate orchestration is susceptible to disruption by factors such as aging, diabetes, and obesity, which can impair the BM niche and consequently affect haematopoiesis. Genetic mutations in Tet2, Dnmt3a, Asxl1, and Jak2 are known to give rise to clonal haematopoiesis of intermediate potential (CHIP), a condition linked to age-related haematological malignancies.

Concurrent inhibition of pBADS99 synergistically improves MEK inhibitor efficacy in KRAS-mutant pancreatic ductal adenocarcinoma.

Therapeutic targeting of KRAS-mutant pancreatic ductal adenocarcinoma (PDAC) has remained a significant challenge in clinical oncology. Direct targeting of KRAS has proven difficult, and inhibition of the KRAS effectors have shown limited success due to compensatory activation of survival pathways. Being a core downstream effector of the KRAS-driven p44/42 MAPK and PI3K/AKT pathways governing intrinsic apoptosis, BAD phosphorylation emerges as a promising therapeutic target.

Vertical pathway inhibition of receptor tyrosine kinases and BAD with synergistic efficacy in triple negative breast cancer.

Aberrant activation of the PI3K/AKT signaling axis along with the sustained phosphorylation of downstream BAD is associated with a poor outcome of TNBC. Herein, the phosphorylated to non-phosphorylated ratio of BAD, an effector of PI3K/AKT promoting cell survival, was observed to be correlated with worse clinicopathologic indicators of outcome, including higher grade, higher proliferative index and lymph node metastasis. The structural optimization of a previously reported inhibitor of BAD-Ser99 phosphorylation was therefore achieved to generate a small molecule inhibiting the phosphorylation of BAD at Ser99 with enhanced potency and improved oral bioavailability.

Development of Piperazine- and Oxazine-Linked Pyrimidines as p65 Subunit Binders of NF-κB in Human Breast Cancer Cells.

Nuclear factor kappa B (NF-κB) is a potential therapeutic target in breast cancer. In the current study, a new class of oxazine- and piperazine-linked pyrimidines was developed as inhibitors of NF-κB, overcoming the complexity of the oxazine structure found in nature and enabling synthesis under laboratory conditions. Among the series of synthesized and tested oxazine-pyrimidine and piperazine-pyrimidine derivatives, compounds and inhibited breast cancer cell (MCF-7) viability with an IC value of 9.

Small molecule inhibition of TFF3 overcomes tamoxifen resistance and enhances taxane efficacy in ER+ mammary carcinoma.

Even though tamoxifen has significantly improved the survival of estrogen receptor positive (ER+) mammary carcinoma (MC) patients, the development of drug resistance with consequent disease recurrence has limited its therapeutic efficacy. Trefoil factor-3 (TFF3) has been previously reported to mediate anti-estrogen resistance in ER+MC. Herein, the efficacy of a small molecule inhibitor of TFF3 (AMPC) in enhancing sensitivity and mitigating acquired resistance to tamoxifen in ER+MC cells was investigated.

Discovery of Hybrid Thiouracil-Coumarin Conjugates as Potential Novel Anti-SARS-CoV-2 Agents Targeting the Virus's Polymerase "RdRp" as a Confirmed Interacting Biomolecule.

The coronavirus (COVID-19) pandemic, along with its various strains, has emerged as a global health crisis that has severely affected humankind and posed a great challenge to the public health system of affected countries. The replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mainly depends on RNA-dependent RNA polymerase (RdRp), a key enzyme that is involved in RNA synthesis. In this regard, we designed, synthesized, and characterized hybrid thiouracil and coumarin conjugates (HTCAs) by ether linkage, which were found to have anti-SARS-CoV-2 properties.

Electrochemical Synthesis of New Isoxazoles and Triazoles Tethered with Thiouracil Base as Inhibitors of Histone Deacetylases in Human Breast Cancer Cells.

Histone deacetylases (HDACs) are an attractive drug target for the treatment of human breast cancer (BC), and therefore, HDAC inhibitors (HDACis) are being used in preclinical and clinical studies. The need to understand the scope of the mode of action of HDACis, as well as the report of the co-crystal structure of HDAC6/SS-208 at the catalytic site, provoked us to develop an isoxazole-based lead structure called 4-(2-(((1-(3,4-dichlorophenyl)-1H-1,2,3-triazol-4-yl)methyl)thio) pyrimidin-4-yl) morpholine () and 1-(2-(((3-(p-tolyl) isoxazol-5-yl)methyl)thio) pyrimidin-4-yl) piperidin-4-one () that targets HDACs in human BC cells. We found that the compound or could inhibit the proliferation of BC cells with an IC value of 8.

Methyl-Thiol-Bridged Oxadiazole and Triazole Heterocycles as Inhibitors of NF-κB in Chronic Myelogenous Leukemia Cells.

Nuclear factor kappa beta (NF-κB) is a transcriptional factor that plays a crucial role in regulating cancer cell proliferation. Therefore, the inhibition of NF-κB activity by small molecules may be beneficial in cancer therapy. In this report, methyl-thiol-bridged oxadiazole and triazole heterocycles were synthesized via click chemistry and it was observed that the lead structure, 2-(((1-(3,4-dichlorophenyl)-1H-1,2,3-triazol-4-yl)methyl)thio)-5-(4-methoxybenzyl)-1,3,4-oxadiazole (), reduced the viability of MCF-7 cells with an IC value of 7.

Discovery of Pyrimidine- and Coumarin-Linked Hybrid Molecules as Inducers of JNK Phosphorylation through ROS Generation in Breast Cancer Cells.

Human epidermal growth factor receptor 2 (HER2)-positive breast cancer exhibits early relapses, poor prognoses, and high recurrence rates. Herein, a JNK-targeting compound has been developed that may be of utility in HER2-positive mammary carcinoma. The design of a pyrimidine-and coumarin-linked structure targeting JNK was explored and the lead structure PC-12 [4-(3-((2-((4-chlorobenzyl)thio) pyrimidin-4-yl)oxy)propoxy)-6-fluoro-2-chromen-2-one ()] was observed to selectively inhibit the proliferation of HER2-positive BC cells.

De Novo Design of Imidazopyridine-Tethered Pyrazolines That Target Phosphorylation of STAT3 in Human Breast Cancer Cells.

In breast cancer (BC), STAT3 is hyperactivated. This study explored the design of imidazopyridine-tethered pyrazolines as a de novo drug strategy for inhibiting STAT3 phosphorylation in human BC cells. This involved the synthesis and characterization of two series of compounds namely, 1-(3-(2,6-dimethylimidazo [1,2-a]pyridin-3-yl)-5-(3-nitrophenyl)-4,5-dihydro-1H-pyrazol-1-yl)-2-(4-(substituted)piperazin-1-yl)ethanone and N-substituted-3-(2,6-dimethylimidazo[1,2-a]pyridin-3-yl)-5-(3-nitrophenyl)-4,5-dihydro-1H-pyrazoline-1-carbothioamides.