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Your search keyword '"Kenneth D. Roth"' showing total 1 results
Start Over Author "Kenneth D. Roth" Publisher american chemical society (acs)
1 results on '"Kenneth D. Roth"'

1. Discovery of N-(6-Fluoro-1-oxo-1,2-dihydroisoquinolin-7-yl)-5-[(3R)-3-hydroxypyrrolidin-1-yl]thiophene-2-sulfonamide (LSN 3213128), a Potent and Selective Nonclassical Antifolate Aminoimidazole-4-carboxamide Ribonucleotide Formyltransferase (AICARFT) Inhibitor Effective at Tumor Suppression in a Cancer Xenograft Model

Author

Alicia Torrado, Shane Atwell, Timothy B. Durham, Njoroge F George, Timothy I. Meier, Brandon J. Margolis, Stefan Jon Thibodeaux, Yu-Hua Hui, Robert Dean Dally, Kevin Robert Fales, Kenneth Jeff Thrasher, James Lee Toth, Jing Wang, Kwame Frimpong, Susan A. Konicek, Yong Wang, Chong Si, Kenneth D. Roth, Matthew Lee, Zhipei Wu, Jefferson R. Mc Cowan, Timothy Alan Shepherd, Sandaruwan Geeganage, and Harold B. Brooks

Subjects
Male, Models, Molecular, 0301 basic medicine, Purine, Ribonucleotide, Mice, Nude, Antineoplastic Agents, Triple Negative Breast Neoplasms, Thiophenes, Phosphoribosylaminoimidazolecarboxamide Formyltransferase, Mice, 03 medical and health sciences, chemistry.chemical_compound, Cell Line, Tumor, Drug Discovery, medicine, Animals, Humans, Breast, Cell Proliferation, Sulfonamides, Phosphoribosylaminoimidazolecarboxamide formyltransferase, Cell growth, Cancer, medicine.disease, Oncolytic virus, 030104 developmental biology, chemistry, Biochemistry, Antifolate, Cancer research, Folic Acid Antagonists, Molecular Medicine, Female, Growth inhibition
Abstract

A hallmark of cancer is unbridled proliferation that can result in increased demand for de novo synthesis of purine and pyrimidine bases required for DNA and RNA biosynthesis. These synthetic pathways are frequently upregulated in cancer and involve various folate-dependent enzymes. Antifolates have a proven record as clinically used oncolytic agents. Our recent research efforts have produced LSN 3213128 (compound 28a), a novel, selective, nonclassical, orally bioavailable antifolate with potent and specific inhibitory activity for aminoimidazole-4-carboxamide ribonucleotide formyltransferase (AICARFT), an enzyme in the purine biosynthetic pathway. Inhibition of AICARFT with compound 28a results in dramatic elevation of 5-aminoimidazole 4-carboxamide ribonucleotide (ZMP) and growth inhibition in NCI-H460 and MDA-MB-231met2 cancer cell lines. Treatment with this inhibitor in a murine based xenograft model of triple negative breast cancer (TNBC) resulted in tumor growth inhibition.

Published
2017
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