Small Molecule Induces Time-Dependent Inhibition of Stat3 Dimerization and DNA-Binding Activity and Regresses Human Breast Tumor Xenografts.

Aberrantly-active signal transducer and activator of transcription (Stat)3 has a causal role in many human cancers and represents a validated anticancer drug target, though it has posed significant challenge to drug development. A new small molecule, JKB887, was identified through library screening and is predicted to interact with Lys591, Arg609 and Pro63 in the phospho-tyrosine (pTyr)-binding pocket of the Stat3 SH2 domain. JKB887 inhibited Stat3 DNA-binding activity in vitro in a time-dependent manner, with IC of 2.

A comprehensive review of remediation strategies for mitigating salt precipitation and enhancing CO injectivity during CO injection into saline aquifers.

Geological CO sequestration is a proven method for mitigating climate change by reducing atmospheric CO levels. However, CO injection often induces salt precipitation, leading to decreased formation permeability, which in turn limits CO injectivity and storage capacity. Conventional approaches, such as freshwater and low-salinity water injection, have been employed to mitigate salt precipitation.

Retraction of "Identification of Purine-Scaffold Small-Molecule Inhibitors of Stat3 Activation by QSAR Studies".

[This retracts the article DOI: 10.1021/ml100224d.].

Experimental and theoretical investigation of the mechanisms of drying during CO injection into saline reservoirs.

A viable CO storage resource must have sufficient storage capacity, reliable containment efficiency and adequate well injectivity. Deep saline formations stand out in terms of storage capacity and containment efficiency. However, formation brine dry-out and salt precipitation in the near well region could impair CO injectivity in deep saline reservoirs, thus reducing their potential for CO storage.

Inhibition of STAT3-ferroptosis negative regulatory axis suppresses tumor growth and alleviates chemoresistance in gastric cancer.

Chemotherapy is still one of the principal treatments for gastric cancer, but the clinical application of 5-FU is limited by drug resistance. Here, we demonstrate that ferroptosis triggered by STAT3 inhibition may provide a novel opportunity to explore a new effective therapeutic strategy for gastric cancer and chemotherapy resistance. We find that ferroptosis negative regulation (FNR) signatures are closely correlated with the progression and chemoresistance of gastric cancer.

Novel potent azetidine-based compounds irreversibly inhibit Stat3 activation and induce antitumor response against human breast tumor growth in vivo.

Signal transducer and activator of transcription (Stat)3 is a valid anticancer therapeutic target. We have discovered a highly potent chemotype that amplifies the Stat3-inhibitory activity of lead compounds to levels previously unseen. The azetidine-based compounds, including H172 (9f) and H182, irreversibly bind to Stat3 and selectively inhibit Stat3 activity (IC 0.

SS-4 is a highly selective small molecule inhibitor of STAT3 tyrosine phosphorylation that potently inhibits GBM tumorigenesis in vitro and in vivo.

Glioblastoma (GBM) is a highly aggressive cancer with a dismal prognosis. Constitutively active STAT3 has a causal role in GBM progression and is associated with poor patient survival. We rationally designed a novel small molecule, SS-4, by computational modeling to specifically interact with STAT3.

Discovery of Novel Azetidine Amides as Potent Small-Molecule STAT3 Inhibitors.

We optimized our previously reported proline-based STAT3 inhibitors into an exciting new series of ()-azetidine-2-carboxamide analogues that have sub-micromolar potencies. , and have STAT3-inhibitory potencies (IC) of 0.55, 0.

RasGRP1 induces autophagy and transformation-associated changes in primary human keratinocytes.

Ras mutations are present in only a subset of sporadic human cutaneous squamous cell carcinomas (cSCC) even though Ras is activated in most. This suggests that other mechanisms of Ras activation play a role in the disease. The aberrant expression of RasGRP1, a guanyl nucleotide exchange factor for Ras, is critical for mouse cSCC development through its ability to increase Ras activity.

STAT3 and GR Cooperate to Drive Gene Expression and Growth of Basal-Like Triple-Negative Breast Cancer.

Breast cancers are divided into subtypes with different prognoses and treatment responses based on global differences in gene expression. Luminal breast cancer gene expression and proliferation are driven by estrogen receptor alpha, and targeting this transcription factor is the most effective therapy for this subtype. By contrast, it remains unclear which transcription factors drive the gene expression signature that defines basal-like triple-negative breast cancer, and there are no targeted therapies approved to treat this aggressive subtype.

27-Hydroxycholesterol Impairs Plasma Membrane Lipid Raft Signaling as Evidenced by Inhibition of IL6-JAK-STAT3 Signaling in Prostate Cancer Cells.

We recently reported that restoring the CYP27A1-27hydroxycholesterol axis had antitumor properties. Thus, we sought to determine the mechanism by which 27HC exerts its anti-prostate cancer effects. As cholesterol is a major component of membrane microdomains known as lipid rafts, which localize receptors and facilitate cellular signaling, we hypothesized 27HC would impair lipid rafts, using the IL6-JAK-STAT3 axis as a model given its prominent role in prostate cancer.

Cytotoxic Sesquiterpenoid Quinones and Quinols, and an 11-Membered Heterocycle, Kauamide, from the Hawaiian Marine Sponge .

Several known sesquiterpenoid quinones and quinols (-), and kauamide (), a new polyketide-peptide containing an 11-membered heterocycle, were isolated from the extracts of the Hawaiian marine sponge . The planar structure of was determined from spectroscopic analyses, and its relative and absolute configurations were established from density functional theory (DFT) calculations of the GIAO NMR shielding tensors, and advanced Marfey's analysis of the -MeLeu residue, respectively. Compounds and showed moderate inhibition of β-secretase 1 (BACE1), whereas - exhibited moderate to potent inhibition of growth of human glioma (U251) cells.

An Unusual Benzoisoquinoline-9-one Derivative and Other Related Compounds with Antiproliferative Activity from Hawaiian Endophytic Fungus sp. FT431.

A new polyketide containing the benzoisoquinoline-9-one moiety, peyronetide A (), and three other new derivatives peyronetides B⁻D (⁻), as well as one known compound () were purified from the cultured broth of the endophytic fungus sp. FT431, which was isolated from the Hawaiian indigenous plant, sp. The structures of the new compounds were determined through the analysis of HRMS and NMR spectroscopic data.

Consensus report of the 8 and 9th Weinman Symposia on Gene x Environment Interaction in carcinogenesis: novel opportunities for precision medicine.

The relative contribution of intrinsic genetic factors and extrinsic environmental ones to cancer aetiology and natural history is a lengthy and debated issue. Gene-environment interactions (G x E) arise when the combined presence of both a germline genetic variant and a known environmental factor modulates the risk of disease more than either one alone. A panel of experts discussed our current understanding of cancer aetiology, known examples of G × E interactions in cancer, and the expanded concept of G × E interactions to include somatic cancer mutations and iatrogenic environmental factors such as anti-cancer treatment.

Linker Variation and Structure-Activity Relationship Analyses of Carboxylic Acid-based Small Molecule STAT3 Inhibitors.

The molecular determinants for the activities of the reported benzoic acid (SH4-54), salicylic acid (BP-1-102), and benzohydroxamic acid (SH5-07)-based STAT3 inhibitors were investigated to design optimized analogues. All three leads are based on an -methylglycinamide scaffold, with its two amine groups condensed with three different functionalities. The three functionalities and the CH group of the glycinamide scaffold were separately modified.

Verbenanone, an octahydro-5H-chromen-5-one from a Hawaiian-Plant Associated Fungus FT431.

A new secondary metabolite verbenanone () with a unique (4a,8a)-octahydro-5H-chromen-5-one moiety has been obtained from the endophytic fungus FT431, which was isolated from the native Hawaiian plant sp. The structure of compound was characterized based on NMR and MS spectroscopic analysis. The absolute configuration (AC) of compound was determined by Mosher acids.

Heliotropiumides A and B, new phenolamides with N-carbamoyl putrescine moiety from Heliotropium foertherianum collected in Hawaii and their biological activities.

Two new compounds heliotropiumides A (1) and B (2), phenolamides each with an uncommon carbamoyl putrescine moiety, were isolated from the seeds of a naturalized Hawaiian higher plant, Heliotropium foertherianum Diane & Hilger in the borage family, which is widely used for the treatment of ciguatera fish poisoning. The structures of compounds 1 and 2 were characterized based on MS spectroscopic and NMR analysis, and DP4+ calculations. The absolute configuration (AC) of compound 1 was determined by comparison of its optical rotation with those reported in literature.

NF-κB inhibitors, unique γ-pyranol-γ-lactams with sulfide and sulfoxide moieties from Hawaiian plant Lycopodiella cernua derived fungus Paraphaeosphaeria neglecta FT462.

LC-UV/MS-based metabolomic analysis of the Hawaiian endophytic fungus Paraphaeosphaeria neglecta FT462 led to the identification of four unique mercaptolactated γ-pyranol-γ-lactams, paraphaeosphaerides E-H (1-4) together with one γ-lactone (5) and the methyl ester of compound 2 (11). The structures of the new compounds (1-5 and 11) were elucidated through the analysis of HRMS and NMR spectroscopic data. The absolute configuration was determined by chemical reactions with sodium borohydride, hydrogen peroxide, α-methoxy-α-(trifluoromethyl)phenylacetyl chlorides (Mosher reagents), and DP4 + NMR calculations.

Bioactive polyprenylated benzophenone derivatives from the fruits extracts of Garcinia xanthochymus.

Two new polycyclic prenylated xanthones (1 and 2) and a new phenylpropanoid glycoside (3), along with seven known compounds (4-10) were isolated from the fruits of Garcinia xanthochymus. The structures were elucidated by 1D- and 2D-NMR, and HRMS experiments. The isolates were evaluated for their inhibitory effects against the viability of U251MG glioblastoma and MDA-MB-231 breast cancer cells that harbor an aberrantly active signal transducer and exhibit activation of transcription 3 (STAT3), and compared to normal NIH3T3 mouse fibroblasts.

A New N-methoxypyridone from the Co-Cultivation of Hawaiian Endophytic Fungi Camporesia sambuci FT1061 and Epicoccum sorghinum FT1062.

A new -methoxypyridone analog (), together with four known compounds, was isolated from the co-culture of Hawaiian endophytic fungi FT1061 and FT1062. The structure of the new compound was elucidated as 11-hydroxy-1-methoxyfusaricide () by extensive spectroscopic analysis and comparison with the literature. The absolute configuration of was determined by comparison with the experimental and calculated ECD spectra.