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Cancers (Basel). 2019 Sep 11;11(9). pii: E1346. doi: 10.3390/cancers11091346.

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

Author information

1
Division of Hematology and Oncology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA. naffourd@ucmail.uc.edu.
2
Division of Hematology and Oncology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA. groverpt@ucmail.uc.edu.
3
Structural Biology Research Center, Institute of Materials Structure Science, High Energy Accelerator Research Organization (KEK), Tokyo 135-0063, Japan. yuhong@post.kek.jp.
4
Department of Accelerator Science, School of High Energy Accelerator Science, SOKENDAI (the Graduate University for Advanced Studies), 1-1 Oho, Tsukuba, Ibaraki 305-0801, Japan. yuhong@post.kek.jp.
5
Division of Hematology and Oncology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA. arunsendil@gmail.com.
6
Division of Hematology and Oncology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA. karawolfe0430@gmail.com.
7
Department of Cancer Biology, University of Cincinnati College of Medicine, OH 45267, USA. karawolfe0430@gmail.com.
8
Department of Neuro-oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA. nkmajd@mdanderson.org.
9
Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA. smithep@ucmail.uc.edu.
10
Molecular Profiling Research Center for Drug Discovery, National Institute of Advanced Science and Technology, 2-3-26 Aomi, Koto, Tokyo 135-0063, Japan. koh-takeuchi@aist.go.jp.
11
Structural Biology Research Center, Institute of Materials Structure Science, High Energy Accelerator Research Organization (KEK), Tokyo 135-0063, Japan. toshiya.senda@kek.jp.
12
Department of Accelerator Science, School of High Energy Accelerator Science, SOKENDAI (the Graduate University for Advanced Studies), 1-1 Oho, Tsukuba, Ibaraki 305-0801, Japan. toshiya.senda@kek.jp.
13
Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima 734-8553, Japan. sakofuji@hiroshima-u.ac.jp.
14
Division of Hematology and Oncology, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267, USA. atsuo.sasaki@uc.edu.
15
Department of Cancer Biology, University of Cincinnati College of Medicine, OH 45267, USA. atsuo.sasaki@uc.edu.
16
Department of Neurosurgery, Brain Tumor Center at UC Gardner Neuroscience Institute, Cincinnati, OH 45267, USA. atsuo.sasaki@uc.edu.
17
Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata 997-0052, Japan. atsuo.sasaki@uc.edu.

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

PMID:
31514446
DOI:
10.3390/cancers11091346
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Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

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