Synthesis and SAR studies of 5-(pyridin-4-yl)-1,3,4-thiadiazol-2-amine derivatives as potent inhibitors of Bloom helicase.

Journal article

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: Rosenthal, A; Dexheimer, T; Gileadi, O; Nguyen, G; Chu, W

• Publication status: Published
• Journal: Bioorganic and medicinal chemistry letters
• Volume: 23
• Issue: 20
• Pages: 5660-5666
• Publication date: 2013-10-01
• DOI: 10.1016/j.bmcl.2013.08.025
• EISSN: 1464-3405
• ISSN: 0960-894X
• Language: English
• Keywords: Structure-Activity Relationship; Phenylurea Compounds; Enzyme Inhibitors; Thiadiazoles; Caco-2 Cells; Amines; Cell Membrane Permeability; RecQ Helicases; Humans