CX-5461-inspired monofunctional platinum RNA polymerase I selective inhibitors with selective lethality in BRCA1-deficient cancer cells?

Inorganic Chemistry Frontiers Pub Date: 2023-06-20 DOI: 10.1039/D3QI00358B

Abstract

Unrestricted cell growth and proliferation of cancer cells correlate with accelerated hyperactivated RNA polymerase I transcription and upregulation of ribosome biogenesis. Herein, we employed 2-(4-methyl-[1,4]diazepan-1-yl)-5-oxo-5H-7-thia-1,11b-diaza-benzo[c]fluorene-6-carboxylic acid (5-methyl-pyrazin-2-ylmethyl)-amide (CX-5461), the first Pol I selective inhibitor with the multitargeting property and synthetical lethality in homologous recombination (HR) deficient cancers, to modify cisplatin, affording two monofunctional platinum Pol I selective inhibitors [PtCl(NH3)2(LH1)]NO3 (P1-Q1) and [PtCl(NH3)2(LH2)]NO3 (P1-Q2) [LH1 = N-(3-(N-methylacetimidamido)propyl)-2-(4-methylpiperazin-1-yl)-5-oxo-5H-benzo[4,5]thiazolo[3,2-a][1,8]naphthyridine-6-carboxamide; LH2 = 2-(4-methyl-1,4-diazepan-1-yl)-N-(3-(N-methylacetimidamido)propyl)-5-oxo-5H-benzo[4,5]thiazolo[3,2-a][1,8]naphthyridine-6-carboxamide]. Our data showed that P1-Q1 and P1-Q2 could preferentially target the Pol I transcription machinery, overcome platinum drug resistance, and display more potent antiproliferative activity in BRCA1-deficient A549 cells. Mechanism studies demonstrated that P1-Q1 and P1-Q2 could effectively accumulate in cancer cells and nucleoli, selectively inhibit Pol I transcription, stimulate nucleolar stress and p53 stabilization, increase intracellular ROS levels, disrupt the mitochondrial membrane potential, and inhibit migration and metastasis, which further lead to cell cycle arrest and apoptosis. Particularly, P1-Q1 could facilitate the formation and stabilization of R-loops, induce severe DNA damage, and trigger ATR/CHK1 and ATM/CHK2 kinase signaling cascades in BRCA1-deficient A549 cells, suggesting that defects in the HR pathway may exacerbate P1-Q1 induced DNA damage and cause synthetic lethality and apoptosis. Our data demonstrated that P1-Q1 and P1-Q2 are distinct from the clinical platinum anticancer drugs in their mechanism of action, and taking advantage of the selective Pol I inhibition, multitargeting property, and synthetic lethality of CX-5461 in HR-deficient cancers to modify platinum-based agents might be a brand-new approach for cancer therapy.

Graphical abstract: CX-5461-inspired monofunctional platinum RNA polymerase I selective inhibitors with selective lethality in BRCA1-deficient cancer cells
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