Transition state analogue design is a frontier technology for targeting specific enzymes in human disease. MT-DADMe-Immucillin-A is an orally available transition state analogue inhibitor for human 5'- methylthioadenosine phosphorylase (MTAP). MTAP inhibition slows or prevents the growth of human head and neck, prostate and human lung cancers in mouse xenografts. Normal tissues are not affected and the inhibitor shows no toxicity against normal cells or to mice. The MTAP inhibitor alters metabolites that are expected to change the ability of DNA methyltransferases to methylate DNA. Cancers are commonly caused by mutations that change gene expression patterns and permit the growth and metastases of tumors. Gene expression patterns leading to cancer are governed, in part, by DNA methylation at regions of the genome rich in CpG bases, called CpG islands. The hypothesis for this research is that MTAP inhibitors alter metabolite levels in cancer tissues to inhibit DNA methylation patterns in humans. Loss of methylation for some of the CpG islands near cancer suppression genes is proposed to alter the gene expression patterns of the cancer cells and to slow or prevent cancer cell growth. This hypothesis will be explored in cultured cell lines and mouse xenograft models of the major human malignancies, lung, breast, prostate colon, head and neck and cervical cancers. Results of tumor growth in mouse xenografts will determine if orally available MTAP inhibitors are effective at suppression of the major human cancers and will identify the altered gene expression patterns. The hypothesis also proposes that inhibition of DNA methylation at CpG islands is mediated through DNA methytransferases. Assays of the human methyltransferases in living cultured cancer cells, cell extracts and in purified complexes of human DNA methyltransferases will be coordinated with DNA methylation patterns and gene expression arrays. New MTAP inhibitors will be synthesized to improve efficacy, oral availability and chemical stability.

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Human cancers result from loss of control of the DNA regions that act as regulators for cell division. New drug candidates are being developed to restore normal control to these cell regulators. The drugs are then tested to see if they prevent human cancers from growing in cultured human cells and in mice. If successful, these studies could lead to new orally available and non-toxic drugs to treat cancers in humans.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Drug Discovery and Molecular Pharmacology Study Section (DMP)
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Lees, Robert G
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Albert Einstein College of Medicine
Schools of Medicine
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Firestone, Ross S; Schramm, Vern L (2017) The Transition-State Structure for Human MAT2A from Isotope Effects. J Am Chem Soc 139:13754-13760
Firestone, Ross S; Cameron, Scott A; Karp, Jerome M et al. (2017) Heat Capacity Changes for Transition-State Analogue Binding and Catalysis with Human 5'-Methylthioadenosine Phosphorylase. ACS Chem Biol 12:464-473
Du, Quan; Wang, Zhen; Schramm, Vern L (2016) Human DNMT1 transition state structure. Proc Natl Acad Sci U S A 113:2916-21
Poulin, Myles B; Schneck, Jessica L; Matico, Rosalie E et al. (2016) Transition state for the NSD2-catalyzed methylation of histone H3 lysine 36. Proc Natl Acad Sci U S A 113:1197-201
Firestone, Ross S; Cameron, Scott A; Tyler, Peter C et al. (2016) Continuous Fluorescence Assays for Reactions Involving Adenine. Anal Chem 88:11860-11867
Poulin, Myles B; Du, Quan; Schramm, Vern L (2015) Chemoenzymatic Synthesis of (36)S Isotopologues of Methionine and S-Adenosyl-L-methionine. J Org Chem 80:5344-7
Schramm, Vern L (2013) Transition States, analogues, and drug development. ACS Chem Biol 8:71-81
Guan, Rong; Tyler, Peter C; Evans, Gary B et al. (2013) Thermodynamic analysis of transition-state features in picomolar inhibitors of human 5'-methylthioadenosine phosphorylase. Biochemistry 52:8313-22
Burgos, Emmanuel S; Gulab, Shivali A; Cassera, Maria B et al. (2012) Luciferase-based assay for adenosine: application to S-adenosyl-L-homocysteine hydrolase. Anal Chem 84:3593-8
Clinch, Keith; Evans, Gary B; Frohlich, Richard F G et al. (2012) Transition state analogue inhibitors of human methylthioadenosine phosphorylase and bacterial methylthioadenosine/S-adenosylhomocysteine nucleosidase incorporating acyclic ribooxacarbenium ion mimics. Bioorg Med Chem 20:5181-7

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