Catalytic [2 + 2 + 2] Cycloaddition of Benzothiophene Dioxides with α,ω-Diynes for the Synthesis of Condensed Polycyclic Compounds

A Rh-catalyzed intermolecular [2 + 2 + 2] cycloaddition of the 2,3-double bond of benzothiophene dioxides with α,ω-diynes gave sulfone-containing cycloadducts in high yields. This is the first example of a catalytic [2 + 2 + 2] cycloaddition that uses the 2,3-double bond of a heterole as an ene moiety. The consecutive reaction of benzodithiophene tetraoxide with 2,3-naphthylene-tethered 1,7-diyne gave an 11-ring condensed polycyclic compound in one pot

Abstract 2076: Low OGG1 protects against the DNA damage induced by MTH1 inhibition

Abstract Increased metabolic activity of cancer cells due to uncontrolled proliferation, often leads to the accumulation of reactive oxygen species (ROS). High ROS can produce tumor-suppressive oxidative DNA damage either directly in the genome or through oxidation of deoxynucleotides that can then be incorporated into DNA. The human 8-oxoguanine glycosylase 1 (OGG1), a base excision repair (BER) enzyme, protects cells from the former by excising genomic 8-oxodG; MutT Homolog 1 (MTH1), the mammalian 8-oxodGTPase, protects cells from the latter by degrading 8-oxo-dGTP. There has been much interest in increasing oxidative DNA damage in tumors as a therapeutic option. Accordingly, inhibitors are being developed that can target both MTH1 and 8-oxodG glycosylase 1 (OGG1) with the speculation that this co-targeting will significantly increase tumor suppression efficiency. Our lab has shown that MTH1 inhibition leads to DNA strand breaks and tumor-suppressive effects in cancers characterized by high MTH1enzymatic activity. Here we assessed whether co-inhibition of OGG1 would provide benefits in tumor-suppressive effects over MTH1 inhibition alone. We first compared OGG1 and MTH1 expression in paired normal versus tumor tissue from lung adenocarcinoma patients and found that, unlike MTH1, OGG1 tends to remain within normal range in cancerous tissue. Similarly, TCGA lung adenocarcinoma patients show minimal OGG1 elevations and a positive correlation between OGG1 and MTH1 mRNA levels even when both are low. This data suggests that tumors with low OGG1 and MTH1 are robustly represented in the tumor continuum. We then co-depleted OGG1/MTH1 in the A549 lung cancer cell line and found this co-depletion led to lower DNA strand breaks and decreased cell senescence over those caused by MTH1 depletion alone. The shMTH1-transduced cells were less sensitive to SU0268, a potent OGG1 inhibitor compared to shGFP-transduced counterparts. We also treated A549 cells with SU0383, a dual OGG1/MTH1 inhibitor. The dual-inhibitor did not consistently increase cytotoxicity either with duration or dose of treatment beyond single inhibitors or combined single MTH1 and OGG1 inhibitors. In conclusion, our findings suggest that the co-inhibition of OGG1 with MTH1 does not produce enhanced therapeutic benefit in tumor cells, and could instead diminish the tumor-inhibitory effects of MTH1 inhibition that arise from induction of DNA strand breaks and p53-induced senescence. Citation Format: Laura Misiara Lincheta, Ling Zhang, Govindi Samaranayake, Nisha Sharma, Dao Nguyen, Yu-Ki Tahara, Eric Kool, Priyamvada Rai. Low OGG1 protects against the DNA damage induced by MTH1 inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2076

OGG1 co-inhibition antagonizes the tumor-inhibitory effects of targeting MTH1

Cancer cells develop protective adaptations against oxidative DNA damage, providing a strong rationale for targeting DNA repair proteins. There has been a high degree of recent interest in inhibiting the mammalian Nudix pyrophosphatase MutT Homolog 1 (MTH1). MTH1 degrades 8-oxo-dGTP, thus limiting its incorporation into genomic DNA. MTH1 inhibition has variously been shown to induce genomic 8-oxo-dG elevation, genotoxic strand breaks in p53-functional cells, and tumor-inhibitory outcomes. Genomically incorporated 8-oxo-dG is excised by the base excision repair enzyme, 8-oxo-dG glycosylase 1 (OGG1). Thus, OGG1 inhibitors have been developed with the idea that their combination with MTH1 inhibitors will have anti-tumor effects by increasing genomic oxidative DNA damage. However, contradictory to this idea, we found that human lung adenocarcinoma with low OGG1 and MTH1 were robustly represented in patient datasets. Furthermore, OGG1 co-depletion mitigated the extent of DNA strand breaks and cellular senescence in MTH1-depleted p53-wildtype lung adenocarcinoma cells. Similarly, shMTH1-transduced cells were less sensitive to the OGG1 inhibitor, SU0268, than shGFP-transduced counterparts. Although the dual OGG1/MTH1 inhibitor, SU0383, induced greater cytotoxicity than equivalent combined or single doses of its parent scaffold MTH1 and OGG1 inhibitors, IACS-4759 and SU0268, this effect was only observed at the highest concentration assessed. Collectively, using both genetic depletion as well as small molecule inhibitors, our findings suggest that OGG1/MTH1 co-inhibition is unlikely to yield significant tumor-suppressive benefit. Instead such co-inhibition may exert tumor-protective effects by preventing base excision repair-induced DNA nicks and p53 induction, thus potentially conferring a survival advantage to the treated tumors. [Display omitted] •Low MTH1/low OGG1 tumors are robustly represented in patient lung adenocarcinoma datasets but low MTH1/high OGG1 are not.•Co-depletion of OGG1 in lung adenocarcinoma cells mitigates shMTH1-induced DNA strand breaks and p53-induced senescence.•p53-null tumor cells have lower OGG1 vs. wt p53 counterparts and are more resistant to MTH1 loss-induced anti-tumor effects.•Pharmacologic co-inhibition of OGG1 and MTH1 does not enhance cytotoxicity over the respective single inhibitors

Potent and Selective Inhibitors of 8-Oxoguanine DNA Glycosylase

The activity of DNA repair enzyme 8-oxoguanine DNA glycosylase (OGG1), which excises oxidized base 8-oxoguanine (8-OG) from DNA, is closely linked to mutagenesis, genotoxicity, cancer, and inflammation. To test the roles of OGG1-mediated repair in these pathways, we have undertaken the development of noncovalent small-molecule inhibitors of the enzyme. Screening of a PubChem-annotated library using a recently developed fluorogenic 8-OG excision assay resulted in multiple validated hit structures, including selected lead hit tetrahydroquinoline 1 (IC50 = 1.7 μM). Optimization of the tetrahydroquinoline scaffold over five regions of the structure ultimately yielded amidobiphenyl compound 41 (SU0268; IC50 = 0.059 μM). SU0268 was confirmed by surface plasmon resonance studies to bind the enzyme both in the absence and in the presence of DNA. The compound SU0268 was shown to be selective for inhibiting OGG1 over multiple repair enzymes, including other base excision repair enzymes, and displayed no toxicity in two human cell lines at 10 μM. Finally, experiments confirm the ability of SU0268 to inhibit OGG1 in HeLa cells, resulting in an increase in accumulation of 8-OG in DNA. The results suggest the compound SU0268 as a potentially useful tool in studies of the role of OGG1 in multiple disease-related pathways

Renal Drug Transporters and Drug Interactions.

Transporters in proximal renal tubules contribute to the disposition of numerous drugs. Furthermore, the molecular mechanisms of tubular secretion have been progressively elucidated during the past decades. Organic anions tend to be secreted by the transport proteins OAT1, OAT3 and OATP4C1 on the basolateral side of tubular cells, and multidrug resistance protein (MRP) 2, MRP4, OATP1A2 and breast cancer resistance protein (BCRP) on the apical side. Organic cations are secreted by organic cation transporter (OCT) 2 on the basolateral side, and multidrug and toxic compound extrusion (MATE) proteins MATE1, MATE2/2-K, P-glycoprotein, organic cation and carnitine transporter (OCTN) 1 and OCTN2 on the apical side. Significant drug-drug interactions (DDIs) may affect any of these transporters, altering the clearance and, consequently, the efficacy and/or toxicity of substrate drugs. Interactions at the level of basolateral transporters typically decrease the clearance of the victim drug, causing higher systemic exposure. Interactions at the apical level can also lower drug clearance, but may be associated with higher renal toxicity, due to intracellular accumulation. Whereas the importance of glomerular filtration in drug disposition is largely appreciated among clinicians, DDIs involving renal transporters are less well recognized. This review summarizes current knowledge on the roles, quantitative importance and clinical relevance of these transporters in drug therapy. It proposes an approach based on substrate-inhibitor associations for predicting potential tubular-based DDIs and preventing their adverse consequences. We provide a comprehensive list of known drug interactions with renally-expressed transporters. While many of these interactions have limited clinical consequences, some involving high-risk drugs (e.g. methotrexate) definitely deserve the attention of prescribers