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Development of Small Molecules That Specifically Inhibit the D-loop Activity of RAD51

Development of Small Molecules That Specifically Inhibit the D-loop Activity of RAD51

Wei Lv, Brian Budke, Michal Pawlowski, Philip P Connell, Alan P Kozikowski

J Med Chem. 2016 May 26;59(10):4511-25.

PMID: 27049177

Abstract:

RAD51 is the central protein in homologous recombination (HR) DNA repair and represents a therapeutic target in oncology. Herein we report a novel class of RAD51 inhibitors that were identified by high throughput screening. In contrast to many previously reported RAD51 inhibitors, our lead compound 1 is capable of blocking RAD51-mediated D-loop formation (IC50 21.3 ± 7.8 μM) at concentrations that do not influence RAD51 binding to ssDNA. In human cells, 1 inhibits HR (IC50 13.1 ± 1.6 μM) without blocking RAD51's ability to assemble into subnuclear foci at sites of DNA damage. We determined that the active constituent of 1 is actually an oxidized derivative (termed RI(dl)-1 or 8) of the original screening compound. Our SAR campaign also yielded RI(dl)-2 (hereafter termed 9h), which effectively blocks RAD51's D-loop activity in biochemical systems (IC50 11.1 ± 1.3 μM) and inhibits HR activity in human cells (IC50 3.0 ± 1.8 μM).

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
ALP1902146751	RI(dl)-2		1902146-75-1 (free base)	Price

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