Structure-Activity Relationships of a Novel Inhibitor of BLM Helicase

Wednesday, October 10, 2012 — Poster Session II
Noon – 2:00 p.m	Natcher Conference Center, Building 45	NCATS	CHEM-13

Authors

• AS Rosenthal
• TS Dexheimer
• G Nguyen
• O Gileadi
• I Hickson
• A Simeonov
• A Jadhav
• DJ Maloney

Abstract

The human genome utilizes a variety of complicated mechanisms of DNA repair in order fight constant mutagenic threats from both exogenous and endogenous sources. The RecQ family of helicases, which includes the BLM enzyme, plays an important function in DNA repair by unwinding complementary strands of duplex DNA and other DNA substrates. Mutations of the BLM gene can result in Bloom’s Syndrome, an autosomal recessive disorder, which leads to cancer predisposition. BLM deficient cells exhibit sensitivities to DNA damaging agents indicating that a selective BLM inhibitor could be useful in potentiating the anticancer activity of these agents. In this work, a quantitative high-throughput screen of >355,000 compounds was conducted using a fluorescence-quenching assay which monitored BLM-catalyzed DNA strand separation. Following extensive medicinal chemistry optimization of the “hit” molecule, ML216 and related analogs were developed to possess sub-micromolar BLM inhibition with desirable pharmacokinetic properties. Several compounds were also found to exhibit selectivity for BLM helicase over related helicases. Moreover, these compounds demonstrated cellular activity by inducing sister chromatid exchanges, a hallmark of Bloom's Syndrome, and via selective inhibition of cell proliferation of BLM+ cells over BLM- cells. This work represents the first reported potent and selective inhibitor of BLM helicase.

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