Design And Synthesis Of A 3,5-Diamino-1,2,4-Triazole As A Lysine Specific Demethylase-1 Inhibitor For Therapeutic Use In Cancer

Allison McLane

School Name

Governor's School for Science and Math

Grade Level

12th Grade

Presentation Topic

Chemistry

Presentation Type

Mentored

Mentor

Mentor: Dr. Woster; Department of Drug Discovery and Organic Synthesis, Medical University of South Carolina

Abstract

Pancreatic Cancer is one of the most lethal of all cancers and new therapeutic treatments are needed. Pancreatic cancer is one of the many cancers in which a chromatin remodeling amine oxidase enzyme, lysine specific demethylase 1 (LSD1) is over expressed. LSD1 is an enzyme that causes the change in histone density in order to control gene suppression. When bonded with a corepressor protein (CoREST) to form the protein complex, LSD1 demethylates the epigenetic markers on histone 3 lysine 4 (H3K4) and silences tumor suppressor genes. These epigenetic modifications allow H3K4 to be a common site for tumor growth in cancerous cells. The epigenetic markers on a histone determine the density of the chromatin complex and whether or not a gene will be read and sequenced. Epigenetic drug discovery is important to the advancement of cancer research because abnormal gene modification can be lethal. Discovered previously by virtual screening, 3,5-diamino-1,2,4-triazole was found to be a very effective LSD1 inhibitor. It is hypothesized that synthetic analogs of 3,5-diamino-1,2,4-triazole as lysine-specific demethylase 1 (LSD1) inhibitors will decrease demethylation of histone lysine residues and increase tumor suppressor gene expression in cancer cells, thereby having a therapeutic use in cancer treatments. To test this hypothesis, synthetic analog N5-(2-(2-(benzyloxy)phenoxy)-6-chlorobenzyl)-1H-1,2,4-triazole-3,5-diamine was successfully synthesized. Future directions for this project are to test this compound against PANC-1 pancreatic cancer cells for LSD1 activity and compare the results to other analogs of 3,5-diamino-1,2,4-triazole for their LSD1 inhibition.

Location

Owens 101

Start Date

4-16-2016 10:00 AM

COinS
 
Apr 16th, 10:00 AM

Design And Synthesis Of A 3,5-Diamino-1,2,4-Triazole As A Lysine Specific Demethylase-1 Inhibitor For Therapeutic Use In Cancer

Owens 101

Pancreatic Cancer is one of the most lethal of all cancers and new therapeutic treatments are needed. Pancreatic cancer is one of the many cancers in which a chromatin remodeling amine oxidase enzyme, lysine specific demethylase 1 (LSD1) is over expressed. LSD1 is an enzyme that causes the change in histone density in order to control gene suppression. When bonded with a corepressor protein (CoREST) to form the protein complex, LSD1 demethylates the epigenetic markers on histone 3 lysine 4 (H3K4) and silences tumor suppressor genes. These epigenetic modifications allow H3K4 to be a common site for tumor growth in cancerous cells. The epigenetic markers on a histone determine the density of the chromatin complex and whether or not a gene will be read and sequenced. Epigenetic drug discovery is important to the advancement of cancer research because abnormal gene modification can be lethal. Discovered previously by virtual screening, 3,5-diamino-1,2,4-triazole was found to be a very effective LSD1 inhibitor. It is hypothesized that synthetic analogs of 3,5-diamino-1,2,4-triazole as lysine-specific demethylase 1 (LSD1) inhibitors will decrease demethylation of histone lysine residues and increase tumor suppressor gene expression in cancer cells, thereby having a therapeutic use in cancer treatments. To test this hypothesis, synthetic analog N5-(2-(2-(benzyloxy)phenoxy)-6-chlorobenzyl)-1H-1,2,4-triazole-3,5-diamine was successfully synthesized. Future directions for this project are to test this compound against PANC-1 pancreatic cancer cells for LSD1 activity and compare the results to other analogs of 3,5-diamino-1,2,4-triazole for their LSD1 inhibition.