A novel TNKS/USP25 inhibitor blocks the Wnt pathway to overcome multi-drug resistance in TNKS-overexpressing colorectal cancer

Modulating Tankyrases(TNKS),interactions with USP25 to promote TNKS degradation,rather than inhibiting their enzymatic activities,is emerging as an alternative/specific approach to inhibit the Wnt/β-catenin pathway.Here,we identified UAT-B,a novel neoantimycin analog isolated from Streptomyces conglobatus,as a small-molecule inhibitor of TNKS-USP25 protein-protein interaction(PPI)to overcome multi-drug resistance in colorectal cancer(CRC).The disruption of TNKS-USP25 complex formation by UAT-B led to a significant decrease in TNKS levels,triggering cell apoptosis through modulation of the Wnt/β-catenin pathway.Importantly,UAT-B successfully inhibited the CRC cells growth that harbored high TNKS levels,as demonstrated in various in vitro and in vivo studies utilizing cell line-based and patient-derived xenografts,as well as APC^(min/+)spontaneous CRC models.Collectively,these findings suggest that targeting the TNKS-USP25 PPI using a small-molecule inhibitor represents a compelling therapeutic strategy for CRC treatment,and UAT-B emerges as a promising candidate for further preclinical and clinical investigations.

Antimicrobial Chlorinated Carbazole Alkaloids from the Sponge-Associated Actinomycete Streptomyces diacarni LHW51701

Four new chlorinated carbazole alkaloids,chlocarbazomycins(CCBs)A-D,were isolated from sponge associated bacterium Streptomyces diacarni LHW51701.Their structures were elucidated via spectroscopic techniques(including HRESIMS,ID&2D NMR),and X-ray crystallographic analysis.Structurally,the 4-chloro coupled with 3-methoxyl substituents in the tricycle nucleus of CCBs A-D and the A/-methoxyl group of CCB-D are rare in naturally occurred tricyclic carbazole alkaloids.Moreover,CCBs A-D do not bear the typical Cl poro-alkyl and C2 meto-methyl side chains of bacterial tricycle carbazoles,suggesting a novel mechanism of aromatic ring formation in biosynthesis.The biological evaluation showed that CCB-C possessed inhibitory activities against pathogenic microorganisms including methicillin-resistant Staphylococcus aureus(MRSA),Mycobacterium smegmatis,Bacillus mycoides,and Candida albicans.

Investigation of carbonyl amidation and O-methylation during biosynthesis of the pharmacophore pyridyl of antitumor piericidins

Piericidins are a large family of bacterialα-pyridone antibiotics with antitumor activities such as their anti-renal carcinoma activity exhibited recently in nude mice.The backbones of piericidins are derived fromβ,δ-diketo carboxylic acids,which are offloaded from a modular polyketide synthase(PKS)and putatively undergo a carbonyl amidation beforeα-pyridone ring formation.The tailoring modifications to theα-pyridone structure mainly include the verified hydroxylation and O-methylation of the C-4′position and an unidentified C-5′O-methylation.Here,we describe a piericidin producer,terrestrial Streptomyces conglobatus,which contains a piericidin biosynthetic gene cluster in two different loci.Deletion of the amidotransferase gene pieD resulted in the accumulation of two fatty acids that should be degraded from the nascent carboxylic acid released by the PKS,supporting the carbonyl amidation function of PieD duringα-pyridone ring formation.Deletion of the O-methyltransferase gene pieB1 led to the production of three piericidin analogues lacking C-5′O-methylation,therefore confirming that PieB1 specifically catalyses the tailoring modification.Moreover,bioactivity analysis of the mutant-derived products provided clues regarding the structure-function relationship for antitumor activity.The work addresses two previously unidentified steps involved in pyridyl pharmacophore formation during piericidin biosynthesis,facilitating the rational bioengineering of the biosynthetic pathway towards valuable antitumor agents.