Abstract
The purine nucleotides ATP and GTP are essential precursors to DNA and RNA synthesis and fundamental for energy metabolism. Although de novo purine nucleotide biosynthesis is increased in highly proliferating cells, such as malignant tumors, it is not clear if this is merely a secondary manifestation of increased cell proliferation. Suggestive of a direct causative effect includes evidence that, in some cancer types, the rate-limiting enzyme in de novo GTP biosynthesis, inosine monophosphate dehydrogenase (IMPDH), is upregulated and that the IMPDH inhibitor, mycophenolic acid (MPA), possesses anti-tumor activity. However, historically, enthusiasm for employing IMPDH inhibitors in cancer treatment has been mitigated by their adverse effects at high treatment doses and variable response. Recent advances in our understanding of the mechanistic role of IMPDH in tumorigenesis and cancer progression, as well as the development of IMPDH inhibitors with selective actions on GTP synthesis, have prompted a reappraisal of targeting this enzyme for anti-cancer treatment. In this review, we summarize the history of IMPDH inhibitors, the development of new inhibitors as anti-cancer drugs, and future directions and strategies to overcome existing challenges.
Highlights
Purine nucleotidesare involved many functions cellular functions (e.g., ATPATP and GTP)are involved in manyincellular includingincluding serving building blocks forRNA, DNA and RNA, sources of energy, enzyme cofactors in metabolic asserving buildingasblocks for DNA and sources of energy, enzyme cofactors in metabolic pathways, and pathways, and components of signal transduction.GTP is a purine nucleoside components of signal transduction
GTP-binding sites within the CBS domains of fungal inosine monophosphate dehydrogenase (IMPDH), which lead to octamerization of the Interestingly, IMPDH is one of several metabolic enzymes that organize into large filaments enzyme and subsequent inhibition of activity [224]
We demonstrated that IMPDH2 upregulation is required to increase GTP concentration that can serve as a reservoir of “feeder” GTP to sustain the needs of high activity of RNA Pol I and III for rRNA and tRNA synthesis, respectively [2]
Summary
Are involved in manyincellular includingincluding serving building blocks forRNA, DNA and RNA, sources of energy, enzyme cofactors in metabolic asserving buildingasblocks for DNA and sources of energy, enzyme cofactors in metabolic pathways, and pathways, and components of signal transduction. [6],mTORC1-activated mTORC1-activated tumors a subset of cell cell lunglung cancers [8].[8] These findingssuggest suggestde de novo novo guanine may a promising therapeutic target some cancers.Mycophenolic. 100 years ago, has shown anti-tumor activity activity in various cancer cell lines and mouse models [9,10,11]. Despite these long-known anti-tumor actions, cell lines and mouse models [9,10,11] These long-known anti-tumor actions, no IMPDH no IMPDH inhibitor has been clinically as drug an anti-cancer drug into large due side inhibitor has been clinically approved as anapproved anti-cancer in large part due sidepart effects at to high effects atdose highand treatment and variable responses. IMPDH inhibitor, mycophenolic than years ago with purification penicillium fungal species culture. (M1), acyl glucuronide (M2), and acyl-glucoside (M3), a CYP450 oxidation product
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