title: Synthesis and SAR studies of 5-(pyridin-4-yl)-1,3,4-thiadiazol-2-amine derivatives as potent inhibitors of Bloom helicase.
abstract: Human cells utilize a variety of complex DNA repair mechanisms in order to combat constant mutagenic and cytotoxic threats from both exogenous and endogenous sources. The RecQ family of DNA helicases, which includes Bloom helicase (BLM), plays an important function in DNA repair by unwinding complementary strands of duplex DNA as well as atypical DNA structures such as Holliday junctions. Mutations of the BLM gene can result in Bloom syndrome, an autosomal recessive disorder associated with cancer predisposition. BLM-deficient cells exhibit increased sensitivity to DNA damaging agents indicating that a selective BLM inhibitor could be useful in potentiating the anticancer activity of these agents. In this work, we describe the medicinal chemistry optimization of the hit molecule following a quantitative high-throughput screen of >355,000 compounds. These efforts lead to the identification of ML216 and related analogs, which possess potent BLM inhibition and exhibit selectivity over related helicases. Moreover, these compounds demonstrated cellular activity by inducing sister chromatid exchanges, a hallmark of Bloom syndrome.
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD, 20892.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Rosenthal
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD, 20892.
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Dexheimer
authors.affiliation: The Structural Genomics Consortium, University of Oxford, Oxford OX3 7DQ, UK.
authors.forename: Opher
authors.initials: O
authors.lastname: Gileadi
authors.affiliation: Department of Medical Oncology, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK.|Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD.
authors.forename: Giang H
authors.initials: GH
authors.lastname: Nguyen
authors.affiliation: Department of Cellular and Molecular Medicine, Nordea Center for Healthy Aging, University of Copenhagen, '2200 Copenhagen N, Denmark.
authors.forename: Wai Kit
authors.initials: WK
authors.lastname: Chu
authors.affiliation: Department of Medical Oncology, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, UK.|Department of Cellular and Molecular Medicine, Nordea Center for Healthy Aging, University of Copenhagen, '2200 Copenhagen N, Denmark.
authors.forename: Ian D
authors.initials: ID
authors.lastname: Hickson
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD, 20892.
authors.forename: Ajit
authors.initials: A
authors.lastname: Jadhav
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD, 20892.
authors.forename: Anton
authors.initials: A
authors.lastname: Simeonov
authors.affiliation: National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD, 20892.
authors.forename: David J
authors.initials: DJ
authors.lastname: Maloney
mesh_terms: D000588:Amines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D010671:Phenylurea Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D053484:RecQ Helicases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013830:Thiadiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: C588146:1-(3-cyano-4-(1H-pyrazol-4-yl)phenyl)-3-(5-(pyridin-4-yl)-1,3,4-thiadiazol-2-yl)urea; D000588:Amines; D004791:Enzyme Inhibitors; D010671:Phenylurea Compounds; D013830:Thiadiazoles; D053484:RecQ Helicases
keywords: ADME; BLM; BS; Bloom helicase; Bloom syndrome; DMF; HR; HTS; Inhibitor; MLM; NADPH; PBS; PEPPSITM-IPr; SAR; SCE; Small molecule; [1,3-Bis(2,6-Diisopropylphenyl)imidazole-2-ylidene](3-chloropyridyl)palladium(II)chloride; absorption, distribution, metabolism and excretion; dimethylformamide; high throughput screen; homologous recombination; mouse liver microsomes; nicotinamide adenine dinucleotide phosphate; phosphate buffered saline; sister chromatid exchanges; structure activity relationship