Discovery of 2(1)-Quinoxalinone Derivatives as Potent and Selective MAT2A Inhibitors for the Treatment of MTAP-Deficient Cancers.

Methionine adenosyltransferase 2A (MAT2A) has emerged as a synthetic lethal drug target in cancers bearing homozygous methylthioadenosine phosphorylase (MTAP) gene deletion. Despite the remarkable progress in the discovery and development of MAT2A inhibitors, current understanding about the selectivity of these compounds toward MTAP-deficient cancers is relatively limited. To improve the selectivity of MAT2A inhibitors for MTAP-deficient cancers remains a significant challenge.

Wheat MIXTA-like Transcriptional Activators Positively Regulate Cuticular Wax Accumulation.

MIXTA-like transcription factors AtMYB16 and AtMYB106 play important roles in the regulation of cuticular wax accumulation in dicot model plant , but there are very few studies on the MIXTA-like transcription factors in monocot plants. Herein, wheat MIXTA-like transcription factors TaMIXTA1 and TaMIXTA2 were characterized as positive regulators of cuticular wax accumulation. The virus-induced gene silencing experiments showed that knock-down of wheat and expressions resulted in the decreased accumulation of leaf cuticular wax, increased leaf water loss rate, and potentiated chlorophyll leaching.

Low-Dose Chemotherapy Preferentially Shapes the Ileal Microbiome and Augments the Response to Immune Checkpoint Blockade by Activating AIM2 Inflammasome in Ileal Epithelial Cells.

Intervention of the gut microbiome is a promising adjuvant strategy in cancer immunotherapy. Chemotherapeutic agents are recognized for their substantial impacts on the gut microbiome, yet their therapeutic potential as microbiome modulators remains uncertain, due to the complexity of microbiome-host-drug interactions. Here, it is showed that low-dose chemotherapy preferentially shapes the ileal microbiome to augment the extraintestinal immune response to anti-programmed death-1 (anti-PD-1) therapy without causing intestinal toxicity.

Discovery of Dual Function Agents That Exhibit Anticancer Activity via Catastrophic Nicotinamide Adenine Dinucleotide Depletion.

Nicotinamide adenine dinucleotide (NAD) is essentially involved in many biological processes of cancer cells, yet chemical intervention of NAD biosynthesis failed to obtain an optimal therapeutic benefit. We herein developed a new strategy to induce catastrophic NAD depletion by concurrently impairing NAD synthesis and promoting NAD consumption. We designed a series of new compounds that conjugate an inhibitor of nicotinamide phosphoribosyltransferase (NAMPT), a rate-limiting enzyme in the NAD salvage pathway, with a DNA-alkylating agent.

Tetrandrine synergizes with MAPK inhibitors in treating KRAS-mutant pancreatic ductal adenocarcinoma via collaboratively modulating the TRAIL-death receptor axis.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and lethal malignancies lacking effective therapies. KRAS mutations that occur in over 90% of PDAC are major oncogenic drivers of PDAC. The MAPK signaling pathway plays a central role in KRAS-driven oncogenic signaling.

A RIPK3-independent role of MLKL in suppressing parthanatos promotes immune evasion in hepatocellular carcinoma.

Mixed lineage kinase domain-like (MLKL) is widely accepted as an executioner of necroptosis, in which MLKL mediates necroptotic signaling and triggers cell death in a receptor-interacting protein kinase 3 (RIPK3)-dependent manner. Recently, it is increasingly noted that RIPK3 is intrinsically silenced in hepatocytes, raising a question about the role of MLKL in hepatocellular carcinoma (HCC). This study reports a previously unrecognized role of MLKL in regulating parthanatos, a programmed cell death distinct from necroptosis.

[Research Progress of Transmembrane Protein Abnormality in Non-Hodgkin's Lymphoma --Review].

Transmembrane protein, also known as integral membrane protein, can be distributed in the lipid bilayer or across the entire membrane, and it plays an important role in cell signal transduction. It has been discovered that multiple transmembrane proteins are involved in the regulation of tumor signals. Recent studies have revealed that the abnormal expression of some transmembrane protein is closely related to the occurrence, development and prognosis of non-Hodgkin's lymphoma (NHL), including programmed cell death protein 1 (PD-1), TMEM30A, NOTCH1, TOLL-like receptor (TLR), sphingosine-1-phosphate receptor, TRAIL, etc.

NAMPT-targeting PROTAC promotes antitumor immunity suppressing myeloid-derived suppressor cell expansion.

Nicotinamide phosphoribosyl transferase (NAMPT) is considered as a promising target for cancer therapy given its critical engagement in cancer metabolism and inflammation. However, therapeutic benefit of NAMPT enzymatic inhibitors appears very limited, likely due to the failure to intervene non-enzymatic functions of NAMPT. Herein, we show that NAMPT dampens antitumor immunity by promoting the expansion of tumor infiltrating myeloid derived suppressive cells (MDSCs) a mechanism independent of its enzymatic activity.

SLC1A1-mediated cellular and mitochondrial influx of R-2-hydroxyglutarate in vascular endothelial cells promotes tumor angiogenesis in IDH1-mutant solid tumors.

Mutant isocitrate dehydrogenase 1 (mIDH1) drives tumorigenesis via producing oncometabolite R-2-hydroxyglutarate (R-2-HG) across various tumor types. However, mIDH1 inhibitors appear only effective in hematological tumors. The therapeutic benefit in solid tumors remains elusive, likely due to the complex tumor microenvironment.

Rational drug design of benzothiazole-based derivatives as potent signal transducer and activator of transcription 3 (STAT3) signaling pathway inhibitors.

The cumulative evidence supports STAT3, a transcriptional mediator of oncogenic signaling, as a therapeutic target in cancer. The development of STAT3 inhibitors remain an active area of research as no inhibitors have yet to be approved for cancer treatment. In a continuing effort to develop more potent STAT3 inhibitors based on our previously identified hit compound 16w, a series of benzothiazole derivatives with unique binding mode in SH2 domain of STAT3 were designed, synthesized and biologically evaluated.