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Insights Into the Binding of PARP Inhibitors to the Catalytic Domain of Human tankyrase-2

Insights Into the Binding of PARP Inhibitors to the Catalytic Domain of Human tankyrase-2

Wei Qiu, Robert Lam, Oleksandr Voytyuk, Vladimir Romanov, Roni Gordon, Simon Gebremeskel, Jakub Vodsedalek, Christine Thompson, Irina Beletskaya, Kevin P Battaile, Emil F Pai, Robert Rottapel, Nickolay Y Chirgadze

Acta Crystallogr D Biol Crystallogr. 2014 Oct;70(Pt 10):2740-53.

PMID: 25286857

Abstract:

The poly(ADP-ribose) polymerase (PARP) family represents a new class of therapeutic targets with diverse potential disease indications. PARP1 and PARP2 inhibitors have been developed for breast and ovarian tumors manifesting double-stranded DNA-repair defects, whereas tankyrase 1 and 2 (TNKS1 and TNKS2, also known as PARP5a and PARP5b, respectively) inhibitors have been developed for tumors with elevated β-catenin activity. As the clinical relevance of PARP inhibitors continues to be actively explored, there is heightened interest in the design of selective inhibitors based on the detailed structural features of how small-molecule inhibitors bind to each of the PARP family members. Here, the high-resolution crystal structures of the human TNKS2 PARP domain in complex with 16 various PARP inhibitors are reported, including the compounds BSI-201, AZD-2281 and ABT-888, which are currently in Phase 2 or 3 clinical trials. These structures provide insight into the inhibitor-binding modes for the tankyrase PARP domain and valuable information to guide the rational design of future tankyrase-specific inhibitors.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
IAR4246444	PARP5A active human			Price

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