Structural basis for the inhibition of poly(ADP-ribose) polymerases 1 and 2 by BMN 673, a potent inhibitor derived from dihydropyridophthalazinone

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‐defici...

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Bibliographic Details
Published in:Acta crystallographica. Section F, Structural biology communications Structural biology communications, 2014-09, Vol.70 (9), p.1143-1149
Main Authors: Aoyagi-Scharber, Mika, Gardberg, Anna S., Yip, Bryan K., Wang, Bing, Shen, Yuqiao, Fitzpatrick, Paul A.
Format: Article
Language:English
Subjects:
Amino Acid Sequence
AUGMENTATION
BMN 673
BONDING
CATALYSIS
CONDENSED MATTER PHYSICS, SUPERCONDUCTIVITY AND SUPERFLUIDITY
CRYSTAL STRUCTURE
DNA
HYDROGEN
Hydrogen Bonding
inhibitor design
INTERACTIONS
Models, Molecular
Molecular Conformation
Molecular Sequence Data
NEOPLASMS
PARP inhibitor
Phthalazines - chemistry
Phthalazines - pharmacology
poly(ADP-ribose) polymerase
Poly(ADP-ribose) Polymerase Inhibitors
Poly(ADP-ribose) Polymerases - chemistry
Structural Communications
WATER
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Summary: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.
ISSN:2053-230X
2053-230X
DOI:10.1107/S2053230X14015088