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Principal Investigator: Taiping Chen
Organization: UNIVERSITY OF TX MD ANDERSON CAN CTR
Fiscal Year: 2024
Award: $227,205
Funding agency: National Cancer Institute
PROJECT SUMMARY/ABSTRACT
DNA cytosine methylation yielding 5-methylcytosine (5mC) is a major epigenetic modification involved in the
regulation of chromatin structure and gene expression. Mammalian DNA methylation is catalyzed by three DNA
methyltransferases (DNMTs), belonging to two structurally and functionally distinct families. DNMT3A and
DNMT3B establish the initial cytosine methylation pattern, whereas DNMT1 maintains that pattern on newly
replicated DNA. Cancer cells exhibit aberrant DNA methylation patterns, including global hypomethylation, which
is associated with low maintenance efficiency, and regional hypermethylation, which is mainly due to abnormal
de novo methylation and/or deficient demethylation. Although the demethylating agents 5-azacytidine and 5-
aza-2'-deoxycytidine (decitabine) have been approved by FDA for treating some hematological malignancies,
these nucleoside analogs incorporate into DNA, leading to substantial DNA damage and cellular toxicity, and
are ineffective in treating solid tumors. Recently, GlaxoSmithKline (GSK) reported the discovery of a new class
of dicyanopyridine-containing DNMT1-selective inhibitors with therapeutic potential. The long-term goal of this
research is to develop a highly potent and selective non-nucleoside DNMT3A/3B inhibitor for cancer treatment.
The objective of this 2-year exploratory project is to identify one or more promising leads for further development.
The rationale is that remedying hypermethylation by inhibiting DNMT3A/3B would reactivate abnormally silenced
genes, including tumor suppressor genes, and thus provide therapeutic benefits for cancer patients. The
proposal is based on preliminary data, generated in the applicants’ laboratories, showing that some
dicyanopyridine-containing derivatives and quinoline-based derivatives can selectively inhibit DNMT3A/3B. The
applicants propose to perform biochemical and structural studies to improve the potency and selectivity of
DNMT3A/3B inhibitors (Aim 1); and validate the compounds for their potency and selectivity using wild-type and
DNMT-deficient mouse embryonic stem cells (mESCs), determine their anti-cancer effects using cancer cell lines
with or without mutations in components of the DNA methylation and demethylation enzymes (DNMT3A, TET2
and IDH1/2), and assess their cytotoxicity using untransformed cell lines (Aim 2). The potential impact of
identifying non-nucleoside DNMT3A/3B inhibitors is likely to be very substantial..
Terms: <2'-deoxy-cytidine><3'-5'-CpG><5 AZC><5-AC><5-Aza-cytidine><5-Azacytidine><5-Azadeoxycytidine><5-deoxyazacytidine><AML - Acute Myeloid Leukemia><AZC><Aberrant DNA Methylation><Acute Myeloblastic Leukemia><Acute Myelocytic Leukemia><Acute Myelogenous Leukemia><Anti-Oncogenes><Antioncogenes><Applications Grants><Assay><Azacitidine><Azacytidine><Base Pairing><Basic Research><Basic Science><Bioassay><Biochemical><Biological Assay><Breast Epithelial Cells><CG-dinucleotide><Cancer Center><Cancer Patient><Cancer Suppressor Genes><Cancer Treatment><Cancer cell line><Cancers><Catalytic Core><Catalytic Domain><Catalytic Region><Catalytic Site><Catalytic Subunit><Cell Death Induction><Cell Line><CellLine><Cellular Expansion><Cellular Growth><Chemicals><Chromatin Structure><Chronic Myelomonocytic Leukemia><Collaborations><Complex><CpG dinucleotide><Crystallization><Cytidine><Cytosine><Cytosine Deoxyribonucleoside><Cytosine Deoxyriboside><Cytosine Ribonucleoside><Cytosine Riboside><DNA><DNA Binding><DNA Binding Interaction><DNA Damage><DNA Injury><DNA Methylation><DNA Methyltransferase><DNA Methyltransferase 3B><DNA Methyltransferase Inhibitor><DNA Modification Methylases><DNA Modification Methyltransferases><DNA Replication><DNA Synthesis><DNA biosynthesis><DNA bound><DNA-Methyltransferases><DNMT3B gene><DNMT3a><DNMT3b><Dacogen><Data><Decitabine><Deoxyazacytidine><Deoxycytidine><Deoxyribonucleic Acid><Development><Dezocitidine><Disease><Disorder><Dnmt><Dysmyelopoietic Syndromes><EC 2.1.1><Embryo><Embryonic><Emerogenes><Enzyme Gene><Enzymes><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Exhibits><FDA approved><Family><Fibroblasts><Follow-Up Studies><Followup Studies><Gene Expression><Gene Inactivation><Gene Silencing><Genetic Alteration><Genetic Change><Genetic defect><Goals><Grant Proposals><Health><Hematologic Cancer><Hematologic Malignancies><Hematologic Neoplasms><Hematological Malignancies><Hematological Neoplasms><Hematological Tumor><Hematopoietic Cancer><Human><Hypermethylation><KO mice><Knock-out Mice><Knockout Mice><Knowledge><Laboratories><Lead><Lytotoxicity><Maintenance><Malignant Cell><Malignant Hematologic Neoplasm><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Tumor><Mediating><Methylation><Methyltransferase><Mice><Mice Mammals><Mission><Modern Man><Modification><Modification Methylases><Mouse Embryonic Progenitor><Mouse Embryonic Stem Cells><Murine><Mus><Mutation><Myelodysplastic Disease><Myelodysplastic Syndromes><NIH><National Institutes of Health><Null Mouse><Onco-Suppressor Genes><Oncogenes-Tumor Suppressors><Oncogenic><Pattern><Pb element><Proliferating><Public Health><Recessive Oncogenes><Refractory Anemia with an Excess of Blasts><Refractory anaemia with excess blasts><Regulation><Reporting><Research><Site-Specific DNA-methyltransferase><Smoldering Leukemia><Solid Neoplasm><Solid Tumor><Strains Cell Lines><System><Testing><Therapeutic><Toxic effect><Toxicities><Transfection><Tumor Suppressing Genes><Tumor Suppressor Genes><United States National Institutes of Health><Vidaza><Work><acute granulocytic leukemia><acute myeloid leukemia><analog><anti-cancer><anti-cancer therapy><biophysical characteristics><biophysical characterization><biophysical measurement><biophysical parameters><biophysical properties><cancer cell><cancer therapy><cancer-directed therapy><cell growth><chemical group><cultured cell line><cytidine monophosphate guanosine><cytidylyl-3'-5'-guanosine><cytosine-guanine dinucleotide><cytotoxicity><demethylation><design><designing><developmental><epigenetically><genome mutation><hDNA methyltransferase 3a><hDNA methyltransferase 3b><heavy metal Pb><heavy metal lead><human DNA><improved><in vitro activity><inhibitor><intercalation><ladakamycin><malignancy><mammalian genome><mammary epithelial cells><methylase><methylation pattern><myelodysplasia><neoplasm/cancer><novel><nucleoside analog><oncosuppressor gene><pre-clinical study><preclinical study><public health relevance><quinoline><transcriptional silencing><transmethylase>