Anti-Tumor Potential of IMP Dehydrogenase Inhibitors: A Century-Long Story

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.

Keywords: GTP; IMPDH; IMPDH inhibitors; anti-tumor; mycophenolic acid; purine synthesis.

Figure 1

Timeline of events in the history of MPA and other IMPDH inhibitors.

Figure 2

MPA: Mechanism of Action. IMPDH catalyzes the rate-limiting, NAD-dependent oxidation of inosine monophosphate (IMP) to xanthosine 5′-monophosphate (XMP), which is an intermediate metabolite in the production of guanosine-triphosphate (GTP). MPA is a potent, selective, reversible, and noncompetitive inhibitor of IMPDH. Abbreviations: SAMP: succinyl-AMP, and PRPP: phosphoribosyl pyrophosphate.

Figure 3

MPA and its metabolites: phenolic MPA-glucuronide (MPAG), phenolic 7-0-glucoside (M1), acyl glucuronide (M2), and acyl-glucoside (M3), a CYP450 oxidation product.

Figure 4

MPA and other IMPDH inhibitors and chemical structures.

Figure 5

Intracellular metabolism of tiazofurin. Tiazofurin is a prodrug that is metabolized intracellularly in two steps to its active form TAD. TAD is an NAD analogue that inhibits IMPDH.

Figure 6

TAD and NAD chemical structures.

Figure 7

Other IMPDH inhibitors of chemical structures.

Figure 8

Activation of FF-10501. FF-10501 is metabolized intracellularly to its active form, FF-10501 ribosylmonophosphate (RMP), which inhibits IMPDH.

Figure 9

Schematics of IMPDH structures. (A) Schematic representation of the human IMPDH2 protein (upper) and monomer of human IMPDH2 structure (lower) (PDB ID: 6i0m). IMPDH structure is shown in cartoons while α-helixes are shown in a coiled model. The CBS domain is colored orange, and the MPDH catalytic domain is shown in light purple. (B) Structural changes of the CBS domain upon ATP (Cyan) and GDP (Red) binding in monomeric IMPDH from Ashbya gossypii. Superposed ATP binding (PDB ID: 5mcp) and GDP binding (PDB ID: 4z87) by using Cα overlap and 243 aa was aligned. A-helixes were shown in a cylindrical model. The CBS domain rotated toward an IMPDH catalytic domain (light blue) significantly when GTP binds to the CBS domain, compared with ATP binding. (C,D) Different octameric forms between ATP binding (C) and GTP binding (D). Two monomers of octameric IMPDH (Gray) are colored orange (CBS domain) and light purple (catalytic domain). The approximate longitudinal dimensions of the octamers are indicated on their side. Comparing to ATP binding (C), the interaction changes between CBS domains upon GTP binding made the octameric structure of human IMPDH2 (D, PDB ID: 6i0o) more compact. Since no ATP-bound structure of human IMPDH has been determined, IMPDH from Ashbya gossypii (PDB ID: 5MCP) is used as the ATP binding model.

Figure 10

IMPDH Ring and Rod (RR) structure is responsive to GTP concentration. A total of 100 μM Acivicin (GMP synthase inhibitor) treatment for 6 hours decreased cellular GTP levels (data not shown) and induced RR structure formation in U87MG cells, which was rescued by 2 hours pre-treatment with 100 μM guanosine that increased cellular GTP (data not shown).