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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.

Original publication

DOI

10.1016/j.bmcl.2013.08.025

Type

Journal article

Journal

Bioorg Med Chem Lett

Publication Date

15/10/2013

Volume

23

Pages

5660 - 5666

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, Amines, Caco-2 Cells, Cell Membrane Permeability, Enzyme Inhibitors, Humans, Phenylurea Compounds, RecQ Helicases, Structure-Activity Relationship, Thiadiazoles