Calcium Channel Blocker Lacidipine Promotes Antitumor Immunity by Reprogramming Tryptophan Metabolism.

Dysfunction of calcium channels is involved in the development and progression of some cancers. However, it remains unclear the role of calcium channel inhibitors in tumor immunomodulation. Here, calcium channel blocker lacidipine is identified to potently inhibit the enzymatic activity and expression of indoleamine 2,3-dioxygenase 1 (IDO1), a rate-limiting enzyme in tryptophan metabolism.

Asymmetric Carbene Insertion into Se-S Bonds by Synergistic Rh(II)/Guanidine Catalysis Involving Chalcogen-Bond Assistance.

The efficient construction of chalcogen-atom-based chiral compounds remains a challenge, despite the importance of organoselenium and organosulfur compounds in life and materials science. Chalcogen atoms can form net attractive interactions called chalcogen bonds, but it is an undeveloped tool to assist asymmetric catalysis. Herein, we report an enantioselective insertion platform to install a stereogenic center bearing selenyl and thiocyano functional groups.

Allosteric inhibition of the tyrosine phosphatase SHP2 enhances the anti-tumor immunity of interferon α through induction of caspase-1-mediated pyroptosis in renal cancer.

Interferon alpha (IFNα) leads to therapeutic effects on various tumors, especially renal cell cancer (RCC), by directly protecting against tumors cell proliferation or indirectly inducing an anti-tumor immune response. However, new combination therapies are needed to enhance the efficacy of IFNα and reduce its adverse effects during long-term treatment. In this study, we found that the anti-proliferative effects of IFNα on RCC cells in vitro and in vivo were greater after the allosteric inhibition of SHP2 by SHP099 than after treatment with enzymatic inhibitors of SHP2.

Discovery of a Covalent Inhibitor of Pro-Caspase-1 Zymogen Blocking NLRP3 Inflammasome Activation and Pyroptosis.

Caspase-1 plays a central role in innate immunity, as its activation by inflammasomes induces the production of proinflammatory cytokines and pyroptosis. However, specific inhibition of the enzymatic activity of this protease is not effective in suppressing inflammation, owing to its enzyme-independent function. Herein, we identified a cyclohexenyl isothiocyanate compound () that potently inhibited caspase-1 activity and suppressed the assembly and activation of the NLRP3 inflammasome and gasdermin-D-mediated pyroptosis.

New eremophilane-type sesquiterpenes from Synotis solidaginea.

Eleven new highly oxygenated eremophilane-type sesquiterpenoids were isolated from the whole plant of Synotis solidaginea, including two pairs of C-8 S/R epimers. The structures of the new compounds were elucidated on the basis of detailed spectroscopic analysis and the absolute configurations of 1 and 9 were confirmed by single-crystal X-ray crystallography using Cu Kα radiation. All the isolates were tested for the inhibition of LPS-stimulated NO production in macrophage-like mouse monocytic leukemia RAW264.

Hunteriasines A - D, tryptamine-derived alkaloids from Hunteria umbellata.

Four undescribed tryptamine-derived alkaloids, hunteriasines A - D, were isolated and identified from Hunteria umbellata (Apocynaceae), together with fifteen known indole alkaloids. The chemical structure and absolute configuration of hunteriasine A were determined by spectroscopic and X-ray crystallographic data analyses. Hunteriasine A, featuring with a unique scaffold comprised of tryptamine and an unprecedented "12-carbon unit" moiety, is a zwitterionic indole-derived and pyridinium-containing alkaloid.

Hexachlorophene, a selective SHP2 inhibitor, suppresses proliferation and metastasis of KRAS-mutant NSCLC cells by inhibiting RAS/MEK/ERK and PI3K/AKT signaling pathways.

Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations account for 35% of the genetic alterations in non-small cell lung cancer (NSCLC). The Src-homology region 2-containing protein tyrosine phosphatase 2 (SHP2), encoded by PTPN11, is closely involved in RAS downstream pathways and development of many tumors by affecting cell proliferation, differentiation, and immunity. Targeting SHP2 with small molecules may be a promising avenue for the treatment of KRAS-mutant (mut) NSCLC.

A small molecule inhibitor of caspase-1 inhibits NLRP3 inflammasome activation and pyroptosis to alleviate gouty inflammation.

Caspase-1 is an integral regulator of innate immunity, which plays a key role in inflammasome activation and the release of pro-inflammatory cytokines. The development of novel non-peptidic small molecule caspase-1 inhibitors is an important strategy for antagonizing excessively activated caspase-1 induced by inflammatory diseases, including gouty arthritis. In the present study, we identified 63 caspase-1 inhibitors, with different structures and potencies, from bioactive compound libraries.

Identification of a Novel TAR RNA-Binding Protein 2 Modulator with Potential Therapeutic Activity against Hepatocellular Carcinoma.

Imbalance miRNAs contribute to tumor formation; therefore, the development of small-molecule compounds that regulate miRNA biogenesis is an important strategy in oncotherapy. Here, (-)-Gomisin M1 (GM) was found to modulate miRNA biogenesis to inhibit the proliferation, migration, and invasion of hepatocellular carcinoma (HCC) cells. GM modulated expression profiles of miRNA and protein in HCC cells and suppressed tumor growth in a mouse model.

A 2-Benzylmalonate Derivative as STAT3 Inhibitor Suppresses Tumor Growth in Hepatocellular Carcinoma by Upregulating β-TrCP E3 Ubiquitin Ligase.

The aberrant activation of a signal transducer and activator of transcription 3 (STAT3) restrains type I interferon (IFN) α/β-induced antiviral responses and is associated with the development of cancer. Designing specific STAT3 inhibitors will thus provide new options for use as IFN therapy. Herein, we identified a novel small molecule, dimethyl 2-(4-(2-(methyl(phenyl(p-tolyl)methyl)amino)ethoxy)benzyl)malonate (CIB-6), which can inhibit the IFN-α-induced interferon stimulated response element (ISRE) luciferase reporter (IC value = 6.