Dataset Information

1,4-napthoquinone-sulfomethylene-glucose conjugates, a novel targeted approach for advanced prostate cancer

ABSTRACT: Rationale: The Warburg effect is a shift from oxidative phosphorylation to aerobic glycolysis accompanied by an enormous increase in glucose uptake into the cancer cell. We have utilized this effect to design a new group of targeted cytotoxic 1,4-naphthoquinones. To optimize the compounds for clinical use, a group of 1,4-naphthoquinone-glucose derivatives conjugated with a novel thiomethylene linker was synthesized and comprehensively evaluated. Methods: Screening experiments for efficacy and selectivity were performed in a newly synthesized library of 32 conjugates. For the most promising compound PeS-9 activity and mode of action were determined in in vitro, ex vivo and in vivo experiments using different models for prostate cancer (PCa) including human cell lines with various resistance profiles as well as patients-derived tumoroids. Additional experiments were carried out to determine the stability of PeS-9 in the blood as well as possible side effects. Results: The screening experiments identified PeS-9 to have a high efficacy in combination with a promising selectivity towards PCa cells. Further testing of hit compound PeS-9 revealed a selective cytotoxic activity conditioned by a GLUT-1-mediated uptake. PeS-9 induced androgen receptor degradation followed by downregulation of its signaling. In addition, increased reactive oxygen species production and enhanced DNA double-strand breaks were observed. Combinational therapy with PARP-inhibitor olaparib resulted in synergistic effects in homologous recombination deficient cells. The underlying mode of PeS-9 cytotoxic action involved mitochondria targeting, leading to a loss of mitochondrial membrane potential, release of cytochrome C and AIF, activation of caspases-3 and -9, PARP cleavage and apoptotic cell death. This process was stipulated by down-regulation of several antiapoptotic factors and induction of endoplasmic reticulum stress. Moreover, drug-induced activation of signaling pathway mediated by kinases p38, JNK1/2, and ERK1/2 was identified as important factor of the cytotoxic activity. The anticancer activity of PeS-9 could be confirmed ex vivo using patients-derived tumoroids as well as in vivo resulting in decreased tumor growth and dissemination of PCa cells to the lungs. No serious side effects were observed in animal models. In human blood, PeS-9 was more stable than the mother compound. Conclusion: In conclusion, we were able to synthesize and characterize PeS-9, a new 1,4-naphthoquinones-glucose derivative conjugated via a thiomethylene linker. This novel targeted approach exhibited potent antitumor activity and selectivity in human PCa cells mediated by the Warburg effect. The simultaneous inhibition of the AR signaling pathway in combination with increased production of reactive oxygen species make it an attractive substance both as a monotherapy and as a combination partner, especially with PARP inhibitors.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Thomas Mair

LAB HEAD: Sergey Dyshlovoy

PROVIDER: PXD052256 | Pride | 2025-04-14

REPOSITORIES: Pride

ACCESS DATA

Dataset's files

Source:

			Action	DRS
	200115_CK_SD_Ctrl_48h_1.raw	Raw
	200115_CK_SD_Ctrl_48h_2_20200125133644.raw	Raw
	200115_CK_SD_Ctrl_48h_3.raw	Raw
	200115_CK_SD_Ctrl_4h_1.raw	Raw
	200115_CK_SD_Ctrl_4h_2.raw	Raw

Items per page:

1 - 5 of 21

Similar Datasets

Project description:There is an unmet need for chemical tools to explore the role of the Mediator complex in human pathologies ranging from cancer to cardiovascular disease. Here we determine that CCT251545 a WNT-pathway inhibitor discovered by cell-based screening is a potent and selective chemical probe for the Mediator complex-associated protein kinases CDK8 and CDK19. CCT251545 is an ATP competitive inhibitor with >100-fold selectivity over 291 other kinases. X-ray crystallography demonstrates Type 1 binding involving insertion of the CDK8 C-terminus into the ligand binding site. In contrast to Type II inhibitors of CDK8/19 CCT251545 displays potent cell-based activity. We show that CCT251545 and close analogues not only alter WNT-pathway regulated gene expression but also other CDK8/19 targets including STAT1-regulated gene expression. Consistent with this we find that phospho-STAT1SER727 is a biomarker of CDK8 kinase activity in vitro and in vivo. Finally we demonstrate in vivo activity of CCT251545 in WNT-dependent tumours. Compound 1,2, 6 and 9 are close analogues of a 3,4,5-trisubstituted pyridine series identified from a high-throughput cell-based reporter assay of WNT signalling. They were shown to be potent and selective inhibitors of the Mediator complex-associated protein kinases CDK8 and CDK19. They are ATP competitive inhibitors with >100-fold selectivity over 291 other kinases. X-ray crystallography demonstrates Type 1 binding involving insertion of the CDK8 C-terminus into the ligand-binding site. A 3D culture model of murine intestinal-derived organoids expressing a transgenic doxycycline-inducible mutant beta-catenin expression following removal of doxycycline results in reduced WNT signalling and was compared to treatment for 24 hours with coumpound 2, 6 and 9. Compound 2 (n=3), compound 6 (n=4), compound 9 (n=3), doxycycline removal (n=4), doxycycline treatment (n=7). Samples were hybridized agianst mouse reference. Compounds 2, 6 and 9 are close analogues of a 3,4,5-trisubstituted pyridine series identified from a high-throughput cell-based reporter assay of WNT signalling. They were shown to be potent and selective inhibitors of the Mediator complex-associated protein kinases CDK8 and CDK19. They are ATP competitive inhibitors with >100-fold selectivity over 291 other kinases. X-ray crystallography demonstrates Type 1 binding involving insertion of the CDK8 C-terminus into the ligand-binding site.

Dataset Information

1,4-napthoquinone-sulfomethylene-glucose conjugates, a novel targeted approach for advanced prostate cancer

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets