The incorporation of acetylated LAP-TGF-ß1 proteins into exosomes promotes TNBC cell dissemination in lung micro-metastasis.

Triple-negative breast cancer (TNBC) stands as the breast cancer subtype with the highest recurrence and mortality rates, with the lungs being the common site of metastasis. The pulmonary microenvironment plays a pivotal role in the colonization of disseminated tumor cells. Herein, this study highlights the crucial role of exosomal LAP-TGF-ß1, the principal form of exosomal TGF-ß1, in reshaping the pulmonary vascular niche, thereby facilitating TNBC lung metastasis. Although various strategies have been developed to block TGF-ß signaling and have advanced clinically, their significant side effects have limited their therapeutic application. This study demonstrates that in lung metastatic sites, LAP-TGF-ß1 within exosomes can remarkably reconfigure the pulmonary vascular niche at lower doses, bolstering the extravasation and colonization of TNBC cells in the lungs. Mechanistically, under the aegis of the acetyltransferase TIP60, a non-canonical KFERQ-like sequence in LAP-TGF-ß1 undergoes acetylation at the K304 site, promoting its interaction with HSP90A and subsequent transport into exosomes. Concurrent inhibition of both HSP90A and TIP60 significantly diminishes the exosomal burden of LAP-TGF-ß1, presenting a promising therapeutic avenue for TNBC lung metastasis. This study not only offers fresh insights into the molecular underpinnings of TNBC lung metastasis but also lays a foundation for innovative therapeutic strategies.

Circular RNA-encoded oncogenic PIAS1 variant blocks immunogenic ferroptosis by modulating the balance between SUMOylation and phosphorylation of STAT1.

BACKGROUND: The clinical response rate to immune checkpoint blockade (ICB) therapy in melanoma remains low, despite its widespread use. Circular non-coding RNAs (circRNAs) are known to play a crucial role in cancer progression and may be a key factor limiting the effectiveness of ICB treatment. METHODS: The circRNAs that were downregulated after coadministration compared with single administration of PD-1 inhibitor administration were identified through RNA-seq and Ribo-seq, and thus the circPIAS1 (mmu_circ_0015773 in mouse, has_circ_0008378 in human) with high protein coding potential was revealed. Fluorescence in situ hybridization (FISH) assays were conducted to determine the localization of circPIAS1 in human and mouse melanoma cells, as well as its presence in tumor and adjacent tissues of patients. Validation through dual-luciferase reporter assay and LC-MS/MS confirmed the ability of circPIAS1 to encode a novel 108 amino acid polypeptide (circPIAS1-108aa). Specific antisense oligonucleotides (ASOs) targeting the junction site of circPIAS1 were developed to reduce its intracellular levels. Proliferation changes in melanoma cells were assessed using CCK8, EdU, and colony formation assays. The impact of circPIAS1-108aa on the ferroptosis process of melanoma cells was studied through GSH, MDA, and C11-BODIPY staining assays. Western Blot, Immunoprecipitation (IP), and Immunoprecipitation-Mass Spectrometry (IP-MS) techniques were employed to investigate the impact of circPIAS1-108aa on the P-STAT1/SLC7A11/GPX4 signaling pathway, as well as its influence on the balance between STAT1 SUMOylation and phosphorylation. Additionally, a melanoma subcutaneous transplanted tumor mouse model was utilized to examine the combined effect of reducing circPIAS1 levels alongside PD-1 inhibitor. RESULTS: Compared with the group treated with PD-1 inhibitor alone, circPIAS1 was significantly down-regulated in the coadministration group and demonstrated higher protein coding potential. CircPIAS1, primarily localized in the nucleus, was notably upregulated in tumor tissues compared to adjacent tissues, where it plays a crucial role in promoting cancer cell proliferation. This circRNA can encode a unique polypeptide consisting of 108 amino acids, through which it exerts its cancer-promoting function and impedes the effectiveness of ICB therapy. Mechanistically, circPIAS1-108aa hinders STAT1 phosphorylation by recruiting SUMO E3 ligase Ranbp2 to enhance STAT1 SUMOylation, thereby reactivating the transduction of the SLC7A11/GPX4 signaling pathway and restricting the immunogenic ferroptosis induced by IFNγ. Furthermore, the combination of ASO-circPIAS1 with PD-1 inhibitor effectively inhibits melanoma growth and significantly enhances the efficacy of immune drugs in vivo. CONCLUSIONS: Our study uncovers a novel mechanism regarding immune evasion in melanoma driven by a unique 108aa peptide encoded by circPIAS1 in melanoma that dramatically hinders immunogenic ferroptosis triggered by ICB therapy via modulating the balance between SUMOylation and phosphorylation of STAT1. This work reveals circPIAS1-108aa as a critical factor limiting the immunotherapeutic effects in melanoma and propose a promising strategy for improving ICB treatment outcomes.

Chemistry and bioactivity of lindenane sesquiterpenoids and their oligomers.

Covering: 1925 to July 2023Among the sesquiterpenoids with rich structural diversity and potential bioactivities, lindenane sesquiterpenoids (LSs) possess a characteristic cis, trans-3,5,6-carbocyclic skeleton and mainly exist as monomers and diverse oligomers in plants from the Lindera genus and Chloranthaceae family. Since the first identification of lindeneol from Lindera strychnifolia in 1925, 354 natural LSs and their oligomers with anti-inflammatory, antitumor, and anti-infective activities have been discovered. Structurally, two-thirds of LSs exist as oligomers with interesting skeletons through diverse polymeric patterns, especially Diels-Alder [4 + 2] cycloaddition. Fascinated by their diverse bioactivities and intriguing polycyclic architectures, synthetic chemists have engaged in the total synthesis of natural LSs in recent decades. In this review, the research achievements related to LSs from 1925 to July of 2023 are systematically and comprehensively summarized, focusing on the classification of their structures, chemical synthesis, and bioactivities, which will be helpful for further research on LSs and their oligomers.

Pt─O Bond Accelerated Cu0/Cu+ Activity for Boosting Low-Energy Bipolar Hydrogen Production.

To address the imperative challenge of producing hydrogen in a low-energy consumption electrocatalytic system, this study emphasizes the utilization of thermodynamically favorable biomass oxidation for achieving energy-efficient hydrogen generation. This research integrates ultralow PtO2-loaded flower-like nanosheets (denoted as PtO2@Cu2O/Cu FNs) with Cu0/Cu+ pairs and Pt─O bonds, thereby yielding substantial enhancement in both hydrogen evolution reaction (HER, -0.042 VRHE at 10 mA cm-2) and furfural oxidation reaction (FFOR, 0.09 VRHE at 10 mA cm-2). As validated by DFT calculations, the dual built-in electric field (BIEF) is elucidated as the driving force behind the enhanced activities, in which Pt─O bonds expedite the HER, while Cu+/Cu0 promotes low-potential FFOR. By coupling the FFOR and HER together, the resulting bipolar-hydrogen production system requires a low power input (0.5072 kWh per m3) for producing H2. The system can generate bipolar hydrogen and high value-added furoic acid, significantly enhancing hydrogen production efficiency and concurrently mitigating energy consumption.

RNA helicase DEAD-box protein 5 alleviates nonalcoholic steatohepatitis progression via tethering TSC complex and suppressing mTORC1 signaling.

BACKGROUND AND AIMS: Nonalcoholic fatty liver disease and its progressive form, nonalcoholic steatohepatitis (NASH), are rapidly becoming the top causes of hepatocellular carcinoma (HCC). Currently, there are no approved therapies for the treatment of NASH. DEAD-box protein 5 (DDX5) plays important roles in different cellular processes. However, the precise role of DDX5 in NASH remains unclear. APPROACH AND RESULTS: DDX5 expression was downregulated in patients with NASH, mouse models with diet-induced NASH (high-fat diet [HFD], methionine- and choline-deficient diet, and choline-deficient HFD), mouse models with NASH-HCC (diethylnitrosamine with HFD), and palmitic acid-stimulated hepatocytes. Adeno-associated virus-mediated DDX5 overexpression ameliorates hepatic steatosis and inflammation, whereas its deletion worsens such pathology. The untargeted metabolomics analysis was carried out to investigate the mechanism of DDX5 in NASH and NASH-HCC, which suggested the regulatory effect of DDX5 on lipid metabolism. DDX5 inhibits mechanistic target of rapamycin complex 1 (mTORC1) activation by recruiting the tuberous sclerosis complex (TSC)1/2 complex to mTORC1, thus improving lipid metabolism and attenuating the NACHT-, leucine-rich-repeat (LRR)-, and pyrin domain (PYD)-containing protein 3  inflammasome activation. We further identified that the phytochemical compound hyperforcinol K directly interacted with DDX5 and prevented its ubiquitinated degradation mediated by ubiquitin ligase (E3) tripartite motif protein 5, thereby significantly reducing lipid accumulation and inflammation in a NASH mouse model. CONCLUSIONS: These findings provide mechanistic insight into the role of DDX5 in mTORC1 regulation and NASH progression, as well as suggest a number of targets and a promising lead compound for therapeutic interventions against NASH.

Stereoselective Synthesis of ß, γ-Fused Bicyclic γ-Ureasultams via an Intramolecular Mannich and aza-Michael Addition Cascade.

A novel approach has been developed for the synthesis of bicyclic ß, γ-fused bicyclic γ-ureasultams containing two consecutive chiral centers through an intramolecular Mannich and aza-Michael addition cascade of alkenyl sulfamides. The straightforward practical procedure and readily available starting materials enable the synthesis of variously substituted ureasultams. In addition, bicyclic γ-ureasultams is a class of potential biotin analogues.

Target Separation and Potential Anticancer Activity of Withanolide-Based Glucose Transporter Protein 1 Inhibitors from Physalis angulata var. villosa.

The glucose transporter 1 (GLUT1) protein is involved in the basal-level absorption of glucose in tumor cells. Inhibiting GLUT1 decreases tumor cell proliferation and induces tumor cell damage. Natural GLUT1 inhibitors have been studied only to a small extent, and the structures of known natural GLUT1 inhibitors are limited to a few classes of natural products. Therefore, discovering and researching other natural GLUT1 inhibitors with novel scaffolds are essential. Physalis angulata L. var. villosa is a plant known as Mao-Ku-Zhi (MKZ). Withanolides are the main phytochemical components of MKZ. MKZ extracts and the components of MKZ exhibited antitumor activity in recent pharmacological studies. However, the antitumor-active components of MKZ and their molecular mechanisms remain unknown. A cell membrane-biomimetic nanoplatform (CM@Fe3O4/MIL-101) was used for target separation of potential GLUT1 inhibitors from MKZ. A new withanolide, physagulide Y (2), together with six known withanolides (1, 3-7), was identified as a potential GLUT1 inhibitor. Physagulide Y was the most potent GLUT1 inhibitor, and its antitumor activity and possible mechanism of action were explored in MCF-7 human cancer cells. These findings advance the development of technologies for the targeted separation of natural products and identify a new molecular framework for the investigation of natural GLUT1 inhibitors.

Withanolides from Physalis angulata var. villosa and the Relative Configurational Revision of Some Known Analogs.

Physalis angulata var. villosa is a plant possessing abundant withanolides, but in-depth research is lacking. In our ongoing study of P. angulata var. villosa, 15 previously undescribed withanolides (1-15), along with 21 known analogs (16-36), were isolated from the whole plant. The structures of the withanolides (1-15) were elucidated based on analysis of their 1D and 2D NMR, HRESIMS, and ECD data. Additionally, the application of γ-gauche effects with the help of ROESY correlations led to the formulation of empirical rules for withanolides with 14-OH/15-OAc to rapidly determine the 14-OH orientations, making it possible to propose configurational revisions of 19 previously reported analogs (1'-19'). Withanolides 1, 4-6, and 10 showed potent cytotoxic activities against three human cancer cell lines (HCT-116, MDA-MB-231, and A549).

Trisarcglaboids A and B, two cytotoxic lindenane sesquiterpenoid trimers with a unique polymerization mode isolated from Sarcandra glabra.

Trisarcglaboids A and B (1 and 2), representing the first example of lindenane sesquiterpenoid trimers repolymerized based on the classical [4 + 2] type dimer, together with known biogenic precursors chlorahololide D (3) and sarcandrolide A (4), were identified as chemical components of the root of Sarcandra glabra. The novel trimeric lindenane sesquiterpenoid skeletons, including their absolute configurations, were characterized using MS, NMR, ECD, and X-ray single crystal diffraction. The proposed Diels-Alder cycloaddition between Δ2(3) of the tiglic acyl group of the classical [4 + 2] type dimer and Δ15(4),5(6) of the third lindenane may serve as the key biogenic step. In addition, compound 1 exerted significant cytotoxicity against five human cancer cell lines with IC50 values ranging from 1 to 7 µM, potentially through blocking Akt phosphorylation and activating the endogenous apoptosis pathway.

Discovery of piperine derivatives as inhibitors of human dihydroorotate dehydrogenase to induce ferroptosis in cancer cells.

Inhibition of human dihydroorotate dehydrogenase (hDHODH) represents a promising strategy for suppressing the proliferation of cancer cells. To identify novel and potent hDHODH inhibitors, a total of 28 piperine derivatives were designed and synthesized. Their cytotoxicities against three human cancer cell lines (NCI-H226, HCT-116, and MDA-MB-231) and hDHODH inhibitory activities were also evaluated. Among them, compound H19, exhibited the strongest inhibitory activities (NCI-H226 IC50 = 0.95 µM, hDHODH IC50 = 0.21 µM). Further pharmacological investigations revealed that H19 exerted anticancer effects by inducing ferroptosis in NCI-H226 cells, with its cytotoxicity being reversed by ferroptosis inhibitors. This was supported by the intracellular growth or decline of ferroptosis markers, including lipid peroxidation, Fe2+, GSH, and 4-HNE. Overall, H19 emerges as a promising hDHODH inhibitor with potential anticancer properties warranting development.

Structurally diverse triterpenoid alkaloids from Buxus rugulosa.

Four new nortriterpenoid alkaloids, namely buxrugulines E-H (1-4), along with five known ones (5-9), were isolated from the twigs and leaves of Buxus rugulosa. Their structures were identified based on extensive NMR data and MS spectroscopic analyses. Our bioassays revealed that compounds 5, 6 and 8 exhibited potent cytotoxicity in vitro against MCF-7 cell lines, with IC50 values ranging from 6.70 to 11.00 µM, respectively.

Mo Migration-Induced Crystalline to Amorphous Conversion and Formation of RuMo/NiMoO4 Heterogeneous Nanoarray for Hydrazine-Assisted Water Splitting at Large Current Density.

Manipulating the atomic structure of the catalyst and tailoring the dissociative water-hydrogen bonding network at the catalyst-electrolyte interface is essential for propelling alkaline hydrogen evolution reactions (HER) and hydrazine oxidation reaction (HzOR), but remains a great challenge. Herein, we constructed an advanced a-RuMo/NiMoO4/NF heterogeneous electrocatalysts with amorphous RuMo alloy nanoclusters anchored to amorphous NiMoO4 skeletons on Ni foam by a heteroatom implantation strategy. Theoretical calculations and in-situ Raman tests show that the amorphous and alloying structure of a-RuMo/NiMoO4/NF not only induces the directional evolution of interfacial H2O, but also lowers the d-band center (from -0.43 to -2.22 eV) of a-RuMo/NiMoO4/NF, the Gibbs free energy of hydrogen adsorption (ΔGH*, from -1.29 to -0.06 eV), and the energy barrier of HzOR (ΔGN2(g) = 1.50 eV to ΔGN2* = 0.47 eV). Profiting from these favorable factors, the a-RuMo/NiMoO4/NF exhibits excellent electrocatalytic performances, especially at large current densities, with an overpotential of 13 and 129 mV to reach 10 and 1000 mA cm-2 for HER. While for HzOR, it needs only -91 and 276 mV to deliver 10 and 500 mA cm-2, respectively. Further, the constructed a-RuMo/NiMoO4/NF||a-RuMo/NiMoO4/NF electrolyzer demands only 7 and 420 mV to afford 10 and 500 mA cm-2.

Structure of the Major G-Quadruplex in the Human EGFR Oncogene Promoter Adopts a Unique Folding Topology with a Distinctive Snap-Back Loop.

EGFR tyrosine kinase inhibitors have made remarkable success in targeted cancer therapy. However, therapeutic resistance inevitably occurred and EGFR-targeting therapy has been demonstrated to have limited efficacy or utility in glioblastoma, colorectal cancer, and hepatocellular carcinoma. Therefore, there is a high demand for the development of new targets to inhibit EGFR signaling. Herein, we found that the EGFR oncogene proximal promoter sequence forms a unique type of snap-back loop containing G-quadruplex (G4), which can be targeted by small molecules. For the first time, we determined the NMR solution structure of this snap-back EGFR-G4, a three-tetrad-core, parallel-stranded G4 with naturally occurring flanking residues at both the 5'-end and 3'-end. The snap-back loop located at the 3'-end region forms a stable capping structure through two stacked G-triads connected by multiple potential hydrogen bonds. Notably, the flanking residues are consistently absent in reported snap-back G4s, raising the question of whether such structures truly exist under in vivo conditions. The resolved EGFR-G4 structure has eliminated the doubt and showed distinct structural features that distinguish it from the previously reported snap-back G4s, which lack the flanking residues. Furthermore, we found that the snap-back EGFR-G4 structure is highly stable and can form on an elongated DNA template to inhibit DNA polymerase. The unprecedented high-resolution EGFR-G4 structure has thus contributed a promising molecular target for developing alternative EGFR signaling inhibitors in cancer therapeutics. Meanwhile, the two stacked triads may provide an attractive site for specific small-molecule targeting.

Mapping the regulatory effects of herbal organic compounds on gut bacteria.

Herbal organic compounds (HOCs) are bioactive natural products from medicinal plants and some traditional Chinese medicines (TCMs). Recently, ingestion of a few HOCs with low bioavailability has been associated with alterations in gut microbiota, but the extent of this phenomenon remains unclear. Here, we systematically screened 481 HOCs against 47 representative gut bacterial strains in vitro and found that almost one-third of the HOCs exhibited unique anticommensal activity. Quinones showed a potent anticommensal activity, while saturated fatty acids exhibited stronger inhibition of the Lactobacillus genus. Flavonoids, phenylpropanoids, terpenoids, triterpenoids, alkaloids and phenols displayed weaker anticommensal activity, but steroids, saccharides and glycosides had hardly any effect on strain growth. Notably, S-configuration HOCs demonstrated stronger anticommensal activity than R-configuration HOCs. The strict screening conditions ensured high accuracy (95%) through benchmarking validation. Additionally, the effects of HOCs on human fecal microbiota profiling were positively correlated with their anticommensal activity against bacterial strains. Molecular and chemical features such as AATS3i and XLogP3 were correlated with the anticommensal activity of the HOCs in the random forest classifier. Finally, we validated that curcumin, a polyhydric phenol with anticommensal activity, improved insulin resistance in HFD mice by modulating the composition and metabolic function of gut microbiota. Our results systematically mapped the profile of HOCs directly affecting human gut bacterial strains, offering a resource for future research on HOC-microbiota interaction, and broadening our understanding of natural product utilization through gut microbiota modulation.

Rearranged Lindenane Sesquiterpenoid Trimers from Chloranthus fortunei: Target Discovery and Biomimetic Conversion.

Seven lindenane-type sesquiterpenoid trimers, including four new ones (1-4) and three known analogues (5-7), were isolated from Chloranthus fortunei guided by high-performance liquid chromatography with photodiode array detection with characteristic absorption at 210 and 350 nm. Their structures, including absolute configurations, were achieved by high-resolution mass spectrometry, nuclear magnetic resonance, electronic circular dichroism, and quantum chemical calculations. Compound 1 was the first example of two lindenane units connected by a C-15-C-15' bond. The 5/7/5-fused ring system in 2 was presumably formed biogenetically by key keto-enol tautomerism and Cope rearrangement from 5. The 5/3/6 carbon skeleton in 3-5 and epi-cyclopropane in 3 and 6 might have originated from trishizukaol A (7) with a normal 3/5/6-fused ring system through vinylcyclopropane rearrangement. The biomimetic conversion from 7 to 3-6 was successfully achieved by adding a 365 nm ultraviolet lamp and a free radical initiator, and 2 was also spontaneously converted to 5 in methanol and CDCl3, which proved the correctness of the structural identification and the speculation described above. Compounds 1-7 exhibited anti-inflammatory activity with IC50 values in the range of 2.90-22.80 µmol/L.

Association of FHL5 and LPA genetic polymorphisms with diabetes mellitus risk: a case-control study.

BACKGROUND: China is one of the countries with the fastest growing prevalence of diabetes mellitus (DM) in the world. This study intended to investigate the association of single nucleotide polymorphisms (SNPs) of FHL5 and LPA with DM risk in the Chinese population. METHODS: This case-control study involved 1,420 Chinese individuals (710 DM patients and 710 controls). Four candidate loci (rs2252816/rs9373985 in FHL5 and rs3124784/rs7765781 in LPA) were successfully screened. The association of SNPs with DM risk was assessed by logistic regression analysis. Differences in clinical characteristics among subjects with different genotypes were analyzed by one-way analysis of variance. RESULTS: Overall analysis indicated that rs3124784 was associated with an increased risk of DM. Stratification analysis showed that rs3124784 significantly increased DM risk in different subgroups (male, non-smoking, non-drinking, and BMI > 24), while rs7765781 increased DM risk only in participants with BMI ≤ 24. Rs2252816 was associated with the course of DM. We also found that rs2252816 GG genotype and rs9373985 GG genotype were linked to the increased cystatin c in DM patients. CONCLUSION: The genetic polymorphisms of LPA may be associated with DM risk in the Chinese population, which will provide useful information for the prevention and diagnosis of DM.

Design, synthesis and mechanism studies of dual EZH2/BRD4 inhibitors for cancer therapy.

Aberrant expression of EZH2 is frequently observed in cancers, and the EZH2 inhibitors are only effective in hematological malignancies and almost noneffective against solid tumors. It has been reported that the combination of EZH2 and BRD4 inhibitors may be a promising strategy to treat solid tumors being insensitive to EZH2 inhibitors. Thus, a series of EZH2/BRD4 dual inhibitors were designed and synthesized. The optimized compound 28, encoded as KWCX-28, was the most potential compound by the SAR studies. Further mechanism studies showed that KWCX-28 inhibited HCT-116 cells proliferation (IC50 = 1.86 µM), induced HCT-116 cells apoptosis, arrested cell cycle arrest at G0/G1 phase and resisted the histone 3 lysine 27 acetylation (H3K27ac) upregulation. Therefore, KWCX-28 was a potential dual EZH2/BRD4 inhibitors for treating solid tumors.

d-chiro-Inositol Derivatives with Multidrug Resistance Reversal Activities from the Fruits of Chisocheton siamensis.

Chisosiamols A-K (1-11), 11 new d-chiro-inositol derivatives, along with a known analogue (12) were isolated from the fruits of Chisocheton siamensis. Their planar structures and relative configurations were elucidated by the comprehensive application of spectroscopic methods, especially from the characteristic coupling constants, and 1H-1H COSY spectra. The absolute configurations of the d-chiro-inositol core were determined using the ECD exciton chirality and X-ray diffraction crystallographic analytical methods. This is the first crystallographic data reported for the d-chiro-inositol derivatives. A structural elucidation strategy mainly combining 1H-1H COSY correlations and ECD exciton chirality for determining the structure of d-chiro-inositol derivatives was developed, which also led to the revisions of previously reported structures. Bioactivity evaluation indicated that chisosiamols A, B, and J can reverse multidrug resistance in MCF-7/DOX cells in the IC50 range of 3.4-6.5 µM (RF: 3.6-7.0).

γ-Glutamyltranspeptidase-Activated Near-Infrared fluorescent probe for visualization of Drug-Induced liver injury.

Drug-induced liver injury (DILI), induced by overdose or chronic administration of drugs, has become the leading cause of acute liver failure. Therefore, an accurate diagnostic method for DILI is critical to improve treatment efficiency. The production of γ-glutamyltranspeptidase (GGT) is closely related to the progression of drug-induced hepatotoxicity. KL-Glu exhibits a prominent GGT-activated NIR fluorescence (734 nm) with a large Stokes shift (137 nm) and good sensitivity/selectivity, making it favorable for real-time detection of endogenous GGT activity. Using this probe, we evaluated the GGT up-regulation under the acetaminophen-induced liver injury model. Moreover, KL-Glu was successfully used to assess liver injury induced by the natural active ingredient triptolide and the effective amelioration upon treatment with N-acetyl cysteine (NAC) or Glutathione (GSH) in cells and in vivo by fluorescent trapping the fluctuation of GGT for the first time. Therefore, the fluorescent probe KL-Glu can be used as a potential tool to explore the function of GGT in the progression of DILI and for the early diagnosis and prognostic evaluation of DILI.

Discovery of dual PARP and CDK6 inhibitors for triple-negative breast cancer with wild-type BRCA.

Inhibition of PARP is synthetic lethal with defects in BRCA, which provide effective targeted therapy strategy for BRCA mutation type of TNBC patients. However, approximately 80% of TNBC patients do not have BRCA mutations. Recent studies have shown that CDK4/6 inhibitors can increase the sensitivity of wild-type BRCA cells to PARP inhibitors. We designed a series of dual PARP and CDK6 inhibitors, and the most promising compound, P4i, showed good inhibitory activity against PARP1 and CDK6 and good inhibitory effects on MDA-MB-231 (IC50 = 1.96 µM), MDA-MB-468 (IC50 = 2.81 µM) and BT-549 (IC50 = 2.37 µM) cells with wild-type BRCA. Compared with Olaparib, the inhibition capacity of the three BRCA wild-type (MDA-MB-231, MDA-MB-468 and BT-549) cells was about 10-20 times higher, and even better than the combination of Olaparib and Palbociclib. As a novel PARP multifunctional molecule, it is a potential compound for the treatment of BRCA wild-type TNBC.