Exploitation of dihydroorotate dehydrogenase (DHODH) and p53 activation as therapeutic targets: A case study in polypharmacology

Abstract

The tenovins are a frequently studied class of compounds capable of inhibiting sirtuin activity, which is thought to result in increased acetylation and protection of the tumor suppressor p53 from degradation. However, as we and other laboratories have shown previously, certain tenovins are also capable of inhibiting autophagic flux, demonstrating the ability of these compounds to engage with more than one target. In this study we present two additional mechanisms by which tenovins are able to activate p53 and kill tumor cells in culture. These mechanisms are the inhibition of a key enzyme of the de novo pyrimidine synthesis pathway, DHODH, and the blockage of uridine transport into cells. These findings hold a three-fold significance; firstly, we demonstrate that tenovins, and perhaps other compounds that activate p53, may activate p53 by more than one mechanism; secondly, that work previously conducted with certain tenovins as SirT1 inhibitors should additionally be viewed through the lens of DHODH inhibition as this is a major contributor to the mechanism of action of the most widely used tenovins; and finally, that small changes in the structure of a small molecule can lead to a dramatic change in the target profile of the molecule even when the phenotypic readout remains static.

Proof-of-principle studies on a strategy to enhance nucleotide imbalance specifically in cancer cells

“…Our research group became interested in pyrimidine nucleotide metabolism after carrying out a cell-based screen for p53 activating compounds that unlike the mdm2 inhibitors, would not stop cells in G2, a feature that promotes genomic instability in normal and cancer cells [2]. Surprisingly, a remarkable proportion of these activators inhibited DHODH, a key enzyme in the de novo synthesis of UMP [2][3][4]. Numerous high quality DHODH inhibitors have been recently described.…”

Dihydroorotate dehydrogenase promotes cell proliferation and suppresses cell death in esophageal squamous cell carcinoma and colorectal carcinoma

“…These findings suggest that there might be regulatory connections between DHODH expression and mutations of TP53 and PTEN . Tenovins was reported to activate p53 and kill cancer cells by inhibiting DHODH activity and blocking uridine transport into cells ( 31 ). The inhibitors of DHODH, tetrahydroindazoles, could suppress cancer cell growth and viability by activating p53 and its downstream genes ( 32 ).…”

The roles of sirtuins in ferroptosis

“…Ferroptosis plays a significant role in tumors, neurodegenerative diseases, cardiovascular and cerebrovascular diseases, metabolic diseases, and respiratory diseases (Galaris et al, 2006;Dixon et al, 2012;Heemels, 2016;El Hout et al, 2018;Ma et al, 2019;Yoshida et al, 2019;Wang et al, 2021a;Cheng et al, 2021;Chen et al, 2022a). For instance, in neoplastic diseases, high ROS levels and high iron contents in cancer cells render them more susceptible to ferroptosis than normal cells due to their high metabolism (Dixon (Dai et al, 2018), Sirtinol (Grozinger et al, 2001), Suramin (Trapp et al, 2007), Tenovin (Botta et al, 2012), Salermide (Lara et al, 2009), Compound 15e (Sundriyal et al, 2017), SirReal2 (Eid et al, 2022), ELT-11c (Disch et al, 2013), Compound 8 (Mahajan et al, 2014), Compound 28e (Yang et al, 2017b), UBCS0137 (Sundriyal et al, 2017), 3′-(3-fluorophenethyloxy)-2anilinobenzamide (Suzuki et al, 2012) SRT2104 (Milne et al, 2007), Resveratrol (Dai et al, 2018), SRT1720 (Milne et al, 2007), SRT3657 (Gräff et al, 2013), SRT1460 (Pacholec et al, 2010), SRT2183 (Pacholec et al, 2010), piceatannol (Gertz et al, 2012), 1,4-DHP derivative (Mai et al, 2009), Ainsliadimer C (Chen et al, 2022c), Scopolin (Yoo et al, 2017), Tenovin-6 (Ladds et al, 2020), CAY10602 (Nayagam et al, 2006), YK-3-237…”