• 2018-07
  • 2018-10
  • 2018-11
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2510 A novel series of DHODH inhibitors was


    A novel series of DHODH inhibitors was developed by us based on a lead that was discovered during a docking procedure and medicinal chemistry exploration. The activity of the initial lead was improved by a QSAR method and yielded low nanomolar inhibitors.
    Introduction The most common metabolic hallmark of malignant tumors (i.e., the “Warburg effect”) is their propensity to metabolize glucose to lactic 2510 at a high rate even in the presence of oxygen. Increased glucose uptake usually reflects an increased rate of glycolysis, with conversion of glucose to lactate and decreased utilization of pyruvate for mitochondrial oxidative phosphorylation (OXPHOS) (Liberti and Locasale, 2016, Zong et al., 2016). Since the seminal studies of Otto Warburg one century ago, biochemical research on cancer cell metabolism has revealed the highly metabolic plasticity of cancer cells. A large number of metabolic profiles have been discovered, from the highly glycolytic phenotype repeatedly observed on fast-growing cell lines (Vander Heiden et al., 2009, Ward and Thompson, 2012) to the completely opposite profile characterized by a higher dependency on OXPHOS, as found in metastasis (Porporato et al., 2014) or a subclass of diffuse B cell lymphomas (Caro et al., 2012). It is now widely accepted that OXPHOS and glycolysis cooperate to sustain the energy demands of cancer cells (Smolková et al., 2011, Ward and Thompson, 2012) and that cancer cells undergo metabolic reprogramming to maintain anabolism through various mechanisms including the deviation of glycolysis, Krebs cycle truncation, and OXPHOS redirection toward lipid and protein synthesis (Jose et al., 2011, Pavlova and Thompson, 2016). The critical role of mitochondria in carcinogenesis and gene regulation was further evidenced by recent studies on various oncometabolites produced by the tricarboxylic acid (TCA) cycle (Galluzzi et al., 2013, Ward and Thompson, 2012) and by the role of glutaminolysis, a biochemical pathway located in mitochondria (Villar et al., 2015). A better understanding of what determines tumor bioenergetics is also crucial for developing adapted metabolic therapies, as currently proposed for isocitrate dehydrogenase (IDH) 1 and 2 mutant tumors (Emadi et al., 2014, Seltzer et al., 2010). Several genetic and biochemical mechanisms underlying the 2510 bioenergetic profiling of tumors have been discovered in the last decade (for review see Hosseini et al., 2017, Obre and Rossignol, 2015), but most of these findings were obtained on established tumors or on mouse models of cancer progression. Indeed, little attention has been given to the bioenergetic profiling of the cancer initiation phase and how it influences further the bioenergetic behavior of tumors. In the present study, we investigated whether metabolic changes could be detected at the initial stages before typical pathological alterations of carcinogenesis occur, the impact of early metabolic changes in skin tumor formation, and whether these changes can be maintained throughout tumor development. Solar ultraviolet B (UVB) radiation is the primary environmental risk factor responsible for the induction of non-melanoma skin cancers (NMSC) including basal cell carcinomas (BCCs) and squamous cell carcinomas (SCCs), the most common types of human malignancies worldwide. An estimate 5.4 million cases of NMSCs were affecting 3.3 million patients among the US population in 2012 (Rogers et al., 2015). A major deleterious effect of UVB is the induction of well-defined structural alterations in DNA, which, in turn, trigger the DNA damage response (DDR) network. DDR involves sensing the damage and then transducing this signal to downstream effectors that elicit the appropriate responses including repair of DNA damage, cell-cycle delay, senescence, and/or apoptosis (Lagerwerf et al., 2011, Surova and Zhivotovsky, 2013). The ultimate fate of cells with damaged DNA is, indeed, dependent on the type and extent of damage and DNA repair capacity (Branzei and Foiani, 2008, Surova and Zhivotovsky, 2013). If not repaired or if misrepaired, UVB-induced DNA damage can ultimately contribute to the development of skin cancers.