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.

IMP dehydrogenase rod/ring structures in acral melanomas

“…Despite extensive efforts showing that many IMPDH inhibitors effectively suppress cancer cell proliferation in vitro and in vivo, no drug that inhibits IMPDH has been approved as anticancer therapy, mainly due to adverse effects upon high dose ingestion, lack of efficacy, or inconsistent response in certain cancer types. A comprehensive review on the topic was recently published (Naffouje et al, ). The increased and heterogeneous frequency of RR structure assembly across diverse sections of ALM specimens indicates that IMPDH activity within tumor microenvironment is increased and under complex regulation.…”

A tale of two tails - efficient profiling of protein degraders by specific functional and target engagement readouts

“…Three of the proteins that had affected thermal stability in response to IMiD treatment belonged to the inosine synthesis pathway: IMPDH1, IMPDH2, and PFAS. The two formers being the therapeutic targets of the immunosuppressant drug Mycophenolic acid 42 . Our finding that the thermal stability of IMPDH1 and IMPDH2 were affected downstream of IMiD treatment might account for the immunomodulatory effects of IMiDs.…”

“…Our finding that the thermal stability of IMPDH1 and IMPDH2 were affected downstream of IMiD treatment might account for the immunomodulatory effects of IMiDs. Also, IMPDH expression is increased in neoplasms 42 , which indicates that the antineoplastic effects of IMiDs could in part stem from modulation of IMPDH function.…”

Phase II, multi-center, open-label, single-arm clinical trial evaluating the efficacy and safety of Mycophenolate Mofetil in patients with high-grade locally advanced or metastatic osteosarcoma (ESMMO): rationale and design of the ESMMO trial

“…It is a prodrug of mycophenolic acid (MPA), a potent inhibitor of inosine monophosphate dehydrogenase (IMPDH) [14,15]. In some cancer in which IMPDH is upregulated, MPA may possess anti-cancer activity [16]. In 2010, Fellenberg et al reported the observed overexpression of IMPDH in metastatic and chemo-resistant osteosarcoma cell lines, and pharmacological inhibition of IMPDH could result in a reduction of cell viability and cell proliferation [17].…”