Gastrin‐releasing peptide receptor (GRPr) plays proliferative and inflammatory roles in living systems. Here, we report a highly selective GRPr antagonist (JMV594)‐tethered iridium(III) complex for ...probing GRPr in living cancer cells and immune cells. This probe exhibited desirable photophysical properties and also displayed negligible cytotoxicity, overcoming the inherent toxicity of the iridium(III) complex. Its long emission lifetime enabled its luminescence signal to be readily distinguished from the interfering fluorescence of organic dyes by using a time‐resolved technique. This probe selectively visualized living cancer cells via specific binding to GRPr, while it also modulated the function of GRPr on TNF‐α secretion in immune cells. To our knowledge, this is the first peptide‐conjugated iridium(III) complex developed as a GRPr bioimaging probe and modulator of GRPr activity. This theranostic agent shows great potential at unmasking the diverse roles of GRPr in living systems.
A JMV594‐conjugated iridium(III) complex is presented as a long‐lived, potent and selective imaging probe for GRPr in GRPr‐positive living cancer cells. This probe enables the discrimination of GRPr‐positive cancer cells from normal cells, while it is also capable of probing the modulatory functions of GRPr in immune cells.
Targeting apoptosis is a principal strategy in the design of anticancer drugs. In recent years, non-platinum-based scaffolds have been exploited as viable candidates for the exploitation of ...anticancer agents with potentially lower toxicity than the widely used cisplatin analogues. This review highlights the latest advances in developing iridium(III) complexes as anticancer agents that act particularly via targeting apoptotic cell death in cancer cells.
Lysine‐specific demethylase 5A (KDM5A) has recently become a promising target for epigenetic therapy. In this study, we designed and synthesized metal complexes bearing ligands with reported ...demethylase and p27 modulating activities. The Rh(III) complex 1 was identified as a direct, selective and potent inhibitor of KDM5A that directly abrogate KDM5A demethylase activity via antagonizing the KDM5A‐tri‐/di‐methylated histone 3 protein–protein interaction (PPI) in vitro and in cellulo. Complex 1 induced accumulation of H3K4me3 and H3K4me2 levels in cells, causing growth arrest at G1 phase in the triple‐negative breast cancer (TNBC) cell lines, MDA‐MB‐231 and 4T1. Finally, 1 exhibited potent anti‐tumor activity against TNBC xenografts in an in vivo mouse model, presumably via targeting of KDM5A and hence upregulating p27. Moreover, complex 1 was less toxic compared with two clinical drugs, cisplatin and doxorubicin. To our knowledge, complex 1 is the first metal‐based KDM5A inhibitor reported in the literature. We anticipate that complex 1 may be used as a novel scaffold for the further development of more potent epigenetic agents against cancers, including TNBC.
A rhodium(III)‐based complex has been discovered as an inhibitor of KDM5A, an epigenetic target for triple‐negative breast cancer. The complex inhibited the KDM5A–H3K4me3 interaction and suppressed proliferation of triple‐negative breast cancer (TNBC) tumors in mice and may be used as a novel scaffold for further development of more potent epigenetic agents against cancers, including TNBC.
Dearomatization of an indole via palladium(0)-catalyzed cross-coupling reaction has been realized. With readily available triphenylphosphine as ligand, various spiroindolenine derivatives have been ...obtained in good to excellent yields, and enantioselective control is also feasible with chiral ligands.
We have designed for the first time a dual-functional luminescent probe and inhibitor of neuraminidase (NA), a key influenza target. The lead iridium(iii) complex exhibited enhanced inhibition ...against NA compared to the FDA-approved antiviral drug, oseltamivir, and could detect NA even in the presence of an autofluorescent background.
Objective
To investigate the safety and application value of combining Laennec extracapsular occlusion with ICG fluorescence imaging in laparoscopic anatomic hepatectomy.
Methods
Complete ...laparoscopic dissection was performed outside the Laennec sheath, blocking Glisson's pedicle of the corresponding liver segment or lobe. An appropriate amount of indocyanine green (ICG) dye was intravenously injected, and the boundary line between the pre‐cut liver segment and liver lobe was identified using fluorescence laparoscopy. Complete resection of the liver segment or lobe was performed based on anatomical markers. Clinical data, including operation time, intraoperative blood loss, postoperative hospital stay, and postoperative complications, were collected.
Results
A total of 14 cases were included in the study, including seven cases of primary liver cancer, three cases of metastatic liver cancer, three cases of intrahepatic bile duct calculi, and one case of hepatic hemangioma. All 14 patients underwent anatomic hepatectomy under fluorescent laparoscopy, with four cases involving the right liver, seven cases involving the left liver, two cases involving the right anterior lobe, and one case involving the right posterior lobe.
Conclusion
Combining laparoscopic follow‐up of the Laennec membrane with Glisson outer sheath block and intraoperative ICG fluorescence imaging provides real‐time guidance for locating the resection boundaries during anatomic hepatectomy. This approach helps in controlling intraoperative bleeding, reducing operation time, and ensuring high safety. It holds significant value in clinical application.
Figure A, B: The dissected liver pedicle was separated along the Laennec membrane, and the target liver pedicle was clamped to block the blood flow into the liver from the pre‐cut liver leaf; C: Peripheral intravenous ICG was injected, and the boundary line of the pre‐resection liver was found under fluorescence laparoscopy.D: The target liver was completely resected along the section of the pre‐cut liver under real‐time fluorescence laparoscopic localization. (A case study of laparoscopic anatomic resection of right posterior lobe of liver).
Dual-functional theranostics are powerful tools that can allow for the in-field understanding of cancer pathology, yet their use is held back by the paucity of suitable theranostics for living ...systems. Moreover, typical
in vitro
screening conditions for probe molecules do not necessarily generate candidates that can function effectively in the natural
in cellulo
environment, limiting their follow-up use in living systems. We introduce herein a general strategy for the development of an iridium(
iii
) theranostic by grafting a well-known inhibitor as a "binding unit" onto an iridium(
iii
) complex precursor as a "signaling unit". To further optimize their emissive properties, we explored the effect of imaging behavior by incorporating different substituents onto the parental "signaling unit". This design concept was validated by a series of tailored iridium(
iii
) theranostics
2a-2h
for the visualization and inhibition of EGFR in living cancer cells. By comprehensively assessing the theranostic potency of
2a-2h
in both
in vitro
and
in cellulo
contexts, probe
2f
containing electron-donating methoxy groups on the "signaling unit" was discovered to be the most promising candidate theranostic with desirable photophysical/chemical properties. Probe
2f
selectively bound to EGFR
in vitro
and
in cellulo
, enabling it to selectively discriminate living EGFR-overexpressing cancer cells from normal cells that express low levels of EGFR with an "always-on" luminescence signal output. In particular, its long-lived lifetime enabled its luminescence signal to be readily distinguished from the interfering fluorescence of organic dyes by using time-resolved techniques. Complex
2f
simultaneously visualized and inhibited EGFR in a dose-dependent manner, leading to a reduction in the phosphorylation of downstream proteins ERK and MEK, and inhibition of the activity of downstream transcription factor AP1. Notably, complex
2f
is comparable to the parental EGFR inhibitor
1b
, in terms of both inhibitory activity against EGFR and cytotoxicity against EGFR-overexpressing cancer cells. This tailored dual-functional iridium(
iii
) theranostic toolkit provides an alternative strategy for the personalized diagnosis and treatment of cancers.
In order to optimise dual-functional theranostics for application in living systems, we developed an iridium(
iii
) theranostic by grafting an inhibitor as a "binding unit" onto an iridium(
iii
) complex precursor as a "signaling unit".
NEDD8-activating enzyme (NAE) is an essential player of the NEDD8 conjugation pathway that regulates protein degradation. Meanwhile, drug repurposing is a cost-efficient strategy to identify new ...therapeutic uses for existing scaffolds. In this report, mitoxantrone (1) was repurposed as an inhibitor of NAE by virtual screening of an FDA-approved drug database. Compound 1 inhibited NAE activity in cell-free and cell-based systems with high selectivity and was competitive with ATP. Furthermore, compound 1 induced apoptosis of colorectal adenocarcinoma cancer cells through inhibiting the degradation of the neddylation substrate p53.
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•Mitoxantrone was repurposed as an inhibitor of NAE by virtual screening.•1 inhibited NAE activity with high selectivity and was competitive with ATP.•1 induced apoptosis through inhibiting the degradation of the neddylation substrate p53.
As protein-protein interactions (PPIs) are highly involved in most cellular processes, the discovery of PPI inhibitors that mimic the structure of the natural protein partners is a promising strategy ...toward the discovery of PPI inhibitors. In this review, we discuss recent advances in the application of virtual screening for identifying mimics of protein partners. The classification and function of the mimicking protein partner inhibitor discovery by virtual screening are described. We anticipate that this review would be of interest to medicinal chemists and chemical biologists working in the field of protein-protein interaction inhibitors or probes.
Melanoma is a very aggressive form of skin cancer. Although BRAF inhibitors have been utilized for melanoma therapy, advanced melanoma patients still face a low five‐year survival rate. Recent ...studies have shown that CRAF can compensate for BRAF depletion via regulating DNA synthesis to remain melanoma proliferation. Hence, targeting CRAF either alone or in combination with other protein pathways is a potential avenue for melanoma therapy. Based on our previously reported CRAF‐selective inhibitor for renal cancer therapy, we have herein discovered an analogue (complex 1) from the reported CRAF library suppresses melanoma cell proliferation and melanoma tumour growth in murine models of melanoma via blocking the S100B and RAF pathways. Intriguingly, we discovered that inhibiting BRAF together with S100B exerts a novel synergistic effect to significantly restore p53 transcription activity and inhibit melanoma cell proliferation, whereas blocking BRAF together with CRAF only had an additive effect. We envision that blocking the pan‐RAF and S100B/p53 pathways might be a novel synergistic strategy for melanoma therapy and that complex 1 is a potential inhibitor against melanoma via blocking the pan‐RAF and S100B pathways.
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