https://pubs.rsc.org/en/content/articlepdf/2019/NP/C8NP00092A

Marine natural products.

Reactive oxygen species (ROS) are a group of short-lived, highly reactive, oxygen-containing molecules that can induce DNA damage and affect the DNA damage response (DDR). There is unequivocal pre-clinical and clinical evidence that ROS influence the genotoxic stress caused by chemotherapeutics agents and ionizing radiation. Recent studies have provided mechanistic insight into how ROS can also influence the cellular response to DNA damage caused by genotoxic therapy, especially in the context of Double Strand Breaks (DSBs). This has led to the clinical evaluation of agents modulating ROS in combination with genotoxic therapy for cancer, with mixed success so far. These studies point to context dependent outcomes with ROS modulator combinations with Chemotherapy and radiotherapy, indicating a need for additional pre-clinical research in the field. In this review, we discuss the current knowledge on the effect of ROS in the DNA damage response, and its clinical relevance.

ROS and the DNA damage response in cancer.

Cell division cycle 25 (CDC25) phosphatases regulate key transitions between cell cycle phases during normal cell division, and in the event of DNA damage they are key targets of the checkpoint machinery that ensures genetic stability. Taking only this into consideration, it is not surprising that CDC25 overexpression has been reported in a significant number of human cancers. However, in light of the significant body of evidence detailing the stringent complexity with which CDC25 activities are regulated, the significance of CDC25 overexpression in a subset of cancers and its association with poor prognosis are proving difficult to assess. We will focus on the roles of CDC25 phosphatases in both normal and abnormal cell proliferation, provide a critical assessment of the current data on CDC25 overexpression in cancer, and discuss both current and future therapeutic strategies for targeting CDC25 activity in cancer treatment.

CDC25 phosphatases in cancer cells: key players? Good targets?

A review on anticancer potential of bioactive heterocycle quinoline.

Redox dysregulation originating from metabolic alterations and dependence on mitogenic and survival signaling through reactive oxygen species represents a specific vulnerability of malignant cells that can be selectively targeted by redox chemotherapeutics. This review will present an update on drug discovery, target identification, and mechanisms of action of experimental redox chemotherapeutics with a focus on pro- and antioxidant redox modulators now in advanced phases of preclinal and clinical development. Recent research indicates that numerous oncogenes and tumor suppressor genes exert their functions in part through redox mechanisms amenable to pharmacological intervention by redox chemotherapeutics. The pleiotropic action of many redox chemotherapeutics that involves simultaneous modulation of multiple redox sensitive targets can overcome cancer cell drug resistance originating from redundancy of oncogenic signaling and rapid mutation. Moreover, some redox chemotherapeutics may function a...

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Redox-Directed Cancer Therapeutics: Molecular Mechanisms and Opportunities

The Cdc25 dual specificity phosphatases have central roles in coordinating cellular signaling processes and cell proliferation, but potent and selective inhibitors are lacking. We experimentally examined the 1990 compound National Cancer Institute Diversity Set and then computationally selected from their 140 000 compound repository 30 quinolinediones of which 8 had in vitro mean inhibitory concentrations <1 microM. The most potent was 6-chloro-7-(2-morpholin-4-ylethylamino)quinoline-5,8-dione (NSC 663284), which was 20- and 450-fold more selective against Cdc25B(2) as compared with VHR or PTP1B phosphatases, respectively. NSC 663284 exhibited mixed competitive kinetics against Cdc25A, Cdc25B(2), and Cdc25C with K(i) values of 29, 95, and 89 nM, respectively. As compared with NSC 663284, the regioisomer 7-chloro-6-(2-morpholin-4-ylethylamino)quinoline-5,8-dione was 3-fold less active against Cdc25B(2) in vitro and less potent as a growth inhibitor of human breast cancer cells. Computational electrostatic potential mapping suggested the need for an electron-deficient 7-position for maximal inhibitor activity. Using a chemical complementation assay, we found that NSC 663284 blocked cellular Erk dephosphorylation caused by ectopic Cdc25A expression.

Discovery and Biological Evaluation of a New Family of Potent Inhibitors of the Dual Specificity Protein Phosphatase CDC25.

Small molecules provide powerful tools to interrogate biological pathways but many important pathway participants remain refractory to inhibitors. For example, Cdc25 dual-specificity phosphatases regulate mammalian cell cycle progression and are implicated in oncogenesis, but potent and selective inhibitors are lacking for this enzyme class. Thus, we evaluated 10,070 compounds in a publicly available chemical repository of the National Cancer Institute for in vitro inhibitory activity against oncogenic, full-length, recombinant human Cdc25B. Twenty-one compounds had mean inhibitory concentrations of 75% were quinones and >40% were of the para-naphthoquinone structural type. Most notable was NSC 95397 (2,3-bis-[2-hydroxyethylsulfanyl]-[1,4]naphthoquinone), which displayed mixed inhibition kinetics with in vitro K(i) values for Cdc25A, -B, and -C of 32, 96, and 40 nM, respectively. NSC 95397 was more potent than any inhibitor of dual specificity phosphatases described previously and 125- to 180-fold more selective for Cdc25A than VH1-related dual-specificity phosphatase or protein tyrosine phosphatase 1b, respectively. Modification of the bis-thioethanol moiety markedly decreased enzyme inhibitory activity, indicating its importance for bioactivity. NSC 95397 showed significant growth inhibition against human and murine carcinoma cells and blocked G(2)/M phase transition. A potential Cdc25 site of interaction was postulated based on molecular modeling with these quinones. We propose that inhibitors based on this chemical structure could serve as useful tools to probe the biological function of Cdc25.

Identification of a Potent and Selective Pharmacophore for Cdc25 Dual Specificity Phosphatase Inhibitors.

Intracellular reduction and oxidation pathways regulate protein functionality through both reversible and irreversible mechanisms. The Cdc25 phosphatases, which control cell cycle progression, are potential subjects of oxidative regulation. Many of the more potent Cdc25 phosphatase inhibitors reported to date are quinones, which are capable of redox cycling. Therefore, we used the previously characterized quinolinedione Cdc25 inhibitor DA3003-1 [NSC 663284 or 6-chloro-7-(2-morpholin-4-yl-ethylamino)-quinoline-5,8-dione] and a newly synthesized congener JUN1111 [7-(2-morpholin-4-yl-ethylamino)-quinoline-5,8-dione] to test the hypothesis that quinone inhibitors of Cdc25 regulate phosphatase activity through redox mechanisms. Like DA3003-1, JUN1111 selectively inhibited Cdc25 phosphatases in vitro in an irreversible, time-dependent manner and arrested cells in the G1 and G2/M phases of the cell cycle. It is noteworthy that both DA3003-1 and JUN1111 directly inhibited Cdc25B activity in cells. Depletion of glutathione increased cellular sensitivity to DA3003-1 and JUN1111, and in vitro Cdc25B inhibition by these compounds was sensitive to pH, catalase, and reductants (dithiothreitol and glutathione), consistent with oxidative inactivation. In addition, both DA3003-1 and JUN1111 rapidly generated intracellular reactive oxygen species. Analysis of Cdc25B by mass spectrometry revealed sulfonic acid formation on the catalytic cysteine of Cdc25B after in vitro treatment with DA3003-1. These results indicate that irreversible oxidation of the catalytic cysteine of Cdc25B is indeed a mechanism by which these quinolinediones inactivate this protein phosphatase.

Redox regulation of Cdc25B by cell-active quinolinediones.

Caulibugulones are novel but poorly characterized cytotoxic isoquinoline quinones and iminoquinones identified in extracts from the marine bryozoan Caulibugula intermis. We now report that the caulibugulones are selective in vitro inhibitors of the Cdc25 family of cell cycle-controlling protein phosphatases compared with either human vaccinia H1-related phosphatase (VHR) or tyrosine phosphatase 1B (PTP1B). The in vitro inhibition of Cdc25B by caulibugulone A was irreversible and attenuated by reducing agents or catalase, consistent with direct oxidation of the enzyme by reactive oxygen species. Mechanistically, caulibugulone A directly inhibited cellular Cdc25B activity, generated intracellular reactive oxygen species and arrested cells in both G1 and G2/M phases of the cell cycle. Caulibugulone A also caused the selective degradation of Cdc25A protein by a process that was independent of reactive oxygen species production, proteasome activity, and the Chk1 signaling pathway. Instead, caulibugulone A stimulated the phosphorylation and subsequent activation of p38 stress kinase, leading to Cdc25A degradation. Thus, caulibugulone inhibition of cellular Cdc25A and B phosphatases occurred through at least two different mechanisms, leading to pronounced cell cycle arrest.

https://molpharm.aspetjournals.org/content/molpharm/early/2006/10/03/mol.106.028589.full.pdf

Independent mechanistic inhibition of cdc25 phosphatases by a natural product caulibugulone.

The marine bryozoan metabolites caulibugulone A–E were prepared from a readily available isoquinoline dione. These natural products were found to be potent and selective inhibitors of the dual specificity phosphatase Cdc25B.

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Beomjun Joo

Papers

Discovery and Biological Evaluation of a New Family of Potent Inhibitors of the Dual Specificity Protein Phosphatase CDC25.

Identification of a Potent and Selective Pharmacophore for Cdc25 Dual Specificity Phosphatase Inhibitors.

Redox regulation of Cdc25B by cell-active quinolinediones.

Independent mechanistic inhibition of cdc25 phosphatases by a natural product caulibugulone.

Synthesis and biological evaluation of caulibugulones A–E