Abstract
Poly(ADP-ribose) polymerases 1 and 2 (PARP1 and PARP2), which are involved in DNA damage response, are targets of anticancer therapeutics. BMN 673 is a novel PARP1/2 inhibitor with substantially increased PARP-mediated tumor cytotoxicity and is now in later-stage clinical development for BRCA-deficient breast cancers. In co-crystal structures, BMN 673 is anchored to the nicotinamide-binding pocket via an extensive network of hydrogen-bonding and π-stacking interactions, including those mediated by active-site water molecules. The novel di-branched scaffold of BMN 673 extends the binding interactions towards the outer edges of the pocket, which exhibit the least sequence homology among PARP enzymes. The crystallographic structural analyses reported here therefore not only provide critical insights into the molecular basis for the exceptionally high potency of the clinical development candidate BMN 673, but also new opportunities for increasing inhibitor selectivity.
Highlights
The family of poly(ADP-ribose) polymerase (PARP) enzymes plays a critical role in the detection and repair of DNA damage
PARP1 is a 113 kDa protein consisting of three functional domains: an N-terminal DNA-binding domain, a central automodification domain and a C-terminal catalytic domain
Extensive structural similarities of the catalytic domain of PARP2 to that of PARP1 were confirmed by the reported structures (Oliver et al, 2004; Karlberg, Hammarstrom et al, 2010)
Summary
The family of poly(ADP-ribose) polymerase (PARP) enzymes plays a critical role in the detection and repair of DNA damage. A 62 kDa PARP2 enzyme, structurally distinct, has a DNA-binding domain and exhibits the highest degree of homology in the catalytic domain to that of PARP1 (Ameet al., 1999). Extensive structural similarities of the catalytic domain of PARP2 to that of PARP1 were confirmed by the reported structures (Oliver et al, 2004; Karlberg, Hammarstrom et al, 2010). In both PARP1 and PARP2 the DNA-binding domain regulates enzymatic activity as a direct response to DNA damage (Hassa & Hottiger, 2008; Yelamos et al, 2008)
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