Cancers have dysfunctional redox regulation resulting in reactive oxygen species production, damaging both DNA and free dNTPs. The MTH1 protein sanitizes oxidized dNTP pools to prevent incorporation of damaged bases during DNA replication. Although MTH1 is non-essential in normal cells, we show that cancer cells require MTH1 activity to avoid incorporation of oxidized dNTPs, resulting in DNA damage and cell death. We validate MTH1 as an anticancer target in vivo and describe small molecules TH287 and TH588 as first-in-class nudix hydrolase family inhibitors that potently and selectively engage and inhibit the MTH1 protein in cells. Protein co-crystal structures demonstrate that the inhibitors bind in the active site of MTH1. The inhibitors cause incorporation of oxidized dNTPs in cancer cells, leading to DNA damage, cytotoxicity and therapeutic responses in patient-derived mouse xenografts. This study exemplifies the non-oncogene addiction concept for anticancer treatment and validates MTH1 as being cancer phenotypic lethal.
SummaryATR and CHK1 maintain cancer cell survival under replication stress and inhibitors of both kinases are currently undergoing clinical trials. As ATR activity is increased after CHK1 inhibition, we hypothesized that this may indicate an increased reliance on ATR for survival. Indeed, we observe that replication stress induced by the CHK1 inhibitor AZD7762 results in replication catastrophe and apoptosis, when combined with the ATR inhibitor VE-821 specifically in cancer cells. Combined treatment with ATR and CHK1 inhibitors leads to replication fork arrest, ssDNA accumulation, replication collapse, and synergistic cell death in cancer cells in vitro and in vivo. Inhibition of CDK reversed replication stress and synthetic lethality, demonstrating that regulation of origin firing by ATR and CHK1 explains the synthetic lethality. In conclusion, this study exemplifies cancer-specific synthetic lethality between two proteins in the same pathway and raises the prospect of combining ATR and CHK1 inhibitors as promising cancer therapy.
Pyrocarbon materials containing various amounts of boron have been prepared by LPCVD from BCl 3 -C 3 H 8 -H 2 precursor mixtures. The growth rate is increased with respect to pure pyrocarbon deposition. By increasing BCl 3 / (C 3 H 8 + BCl 3 ) ratio up to 85%, the incorporation of boron can reach 33 at.%. A small amount of boron (e.g. 8 at.%) highly enhances the anisotropy of pyrocarbon, as evidenced by optical microscopy, X-ray diffraction and transmission electron microscopy (selected area diffraction and lattice fringes techniques). X-ray photoelectron spectroscopy has shown that a large fraction of the boron atoms are included by substitution in the carbon layers, the remaining boron atoms belongs to a boron-rich amorphous part of the material. As boron content increases beyond 8 at.%, the anisotropy of the boron-rich pyrocarbon decreases, due to the limited growth and stacking of the carbon layers. Also, amorphous boron-rich regions are more and more abundant as the total amount of boron increases. The oxidation resistance of the C(B) materials is better than that of pure pyrocarbon. It is mainly due to the improvement of the structural organization for the low boron content materials and to the coating of the whole material with a stable boron oxide for materials with a higher boron content.
International audienceThe difficulty in using above 2000°C in an oxidizing atmosphere C/C composites as structural components is their poor life time. The solution proposed here consisted in combining two refractory carbides, hafnium and silicon carbides, in coating with a complex architecture, named a three dimensional coating, over a C/C substrate. Such a coating protects the C/C composite at 2050°C under air. The oxidation of the coating leads to the formation of a Si x O y Hf z hafnium-containing silicate liquid, combined with HfO 2(s). This liquid limits oxygen diffusion more than pure SiO 2 does, so it is a better protection against oxidation. Furthermore, HfO 2(s) acts as a grip holding Si x O y Hf z in place. From these results, an oxidation mechanism is proposed and discussed
pH-Sensitive linkers designed to undergo selective hydrolysis at acidic pH compared to physiological pH can be used for the selective release of therapeutics at their site of action. In this paper, the hydrolytic cleavage of a wide variety of molecular structures that have been reported for their use in pH-sensitive delivery systems was examined. A wide variety of hydrolytic stability profiles were found among the panel of tested chemical functionalities. Even within a structural family, a slight modification of the substitution pattern has an unsuspected outcome on the hydrolysis stability. This work led us to establish a first classification of these groups based on their reactivities at pH 5.5 and their relative hydrolysis at pH 5.5 vs. pH 7.4. From this classification, four representative chemical functions were selected and studied in-vitro. The results revealed that only the most reactive functions underwent significant lysosomal cleavage, according to flow cytometry measurements. These last results question the acid-based mechanism of action of known drug release systems and advocate for the importance of an in-depth structure-reactivity study, using a tailored methodology, for the rational design and development of bio-responsive linkers.
The dCTPase pyrophosphatase 1 (dCTPase) regulates the intracellular nucleotide pool through hydrolytic degradation of canonical and noncanonical nucleotide triphosphates (dNTPs). dCTPase is highly expressed in multiple carcinomas and is associated with cancer cell stemness. Here we report on the development of the first potent and selective dCTPase inhibitors that enhance the cytotoxic effect of cytidine analogues in leukemia cells. Boronate 30 displays a promising in vitro ADME profile, including plasma and mouse microsomal half-lives, aqueous solubility, cell permeability and CYP inhibition, deeming it a suitable compound for in vivo studies.
The blood fluke Schistosoma mansoni is the causative agent of the intestinal form of schistosomiasis (or bilharzia). Emergence of Schistosoma mansoni with reduced sensitivity to praziquantel, the drug currently used to treat this neglected disease, has underlined the need for development of new strategies to control schistosomiasis. Our ability to screen drug libraries for antischistosomal compounds has been hampered by the lack of validated S. mansoni targets. In the present work, we describe a virtual screening approach to identify inhibitors of S. mansoni NAD(+) catabolizing enzyme (SmNACE), a receptor enzyme suspected to be involved in immune evasion by the parasite at the adult stage. Docking of commercial libraries into a homology model of the enzyme has led to the discovery of two in vitro micromolar inhibitors. Further structure-activity relationship studies have allowed a 3-log gain in potency, accompanied by a largely enhanced selectivity for the parasitic enzyme over the human homologue CD38.
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