Structural Basis of Selective Inhibition of Human Tankyrases

Narwal, Mohit; Venkannagari, Harikanth; Lehtiö, L.

doi:10.1021/jm201510p

Cited by 126 publications

(148 citation statements)

References 33 publications

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“…The D-loop is very dynamic and often adopts new conformations in order to accommodate the inhibitors. 10 As compound 29 is a potent tankyrase inhibitor, it is possible that some of the observed clinical effects could be due to tankyrase inhibition especially in cases where β-catenin expression is enhanced. 20,21 Compound 10 was designed to mimic NAD + and to bind to the substrate NAD + site of ARTD1.…”

Section: Acs Medicinal Chemistry Lettersmentioning

confidence: 99%

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Evaluation and Structural Basis for the Inhibition of Tankyrases by PARP Inhibitors

Haikarainen

Narwal

Joensuu

et al. 2013

ACS Med. Chem. Lett.

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Tankyrases, an enzyme subfamily of human poly(ADP-ribosyl)polymerases, are potential drug targets especially against cancer. We have evaluated inhibition of tankyrases by known PARP inhibitors and report five cocrystal structures of the most potent compounds in complex with human tankyrase 2. The inhibitors include the small general PARP inhibitors Phenanthridinone, PJ-34, and TIQ-A as well as the more advanced inhibitors EB-47 and rucaparib. The compounds anchor to the nicotinamide subsite of tankyrase 2. Crystal structures reveal flexibility of the ligand binding site with implications for drug development against tankyrases and other ADP-ribosyltransferases. EB-47 mimics the substrate NAD + and extends from the nicotinamide to the adenosine subsite. The clinical ARTD1 inhibitor candidate rucaparib was the most potent tankyrase inhibitor identified (24 and 14 nM for tankyrases), which indicates that inhibition of tankyrases would affect the cellular responses of this compound.

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Section: Acs Medicinal Chemistry Lettersmentioning

confidence: 99%

“…Also other recently discovered inhibitors form this stacking interaction. 10,23,24 As the subsite is conserved in tankyrases, this could indicate a unique binding mode of the substrate in tankyrases although both orientations of the adenosine are possible.…”

Section: Acs Medicinal Chemistry Lettersmentioning

confidence: 99%

Evaluation and Structural Basis for the Inhibition of Tankyrases by PARP Inhibitors

Haikarainen

Narwal

Joensuu

et al. 2013

ACS Med. Chem. Lett.

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“…2, 16 Some of their functions are specific to one or other isoform, but the two tankyrases can act redundantly for many. Thus, in designing a therapeutic inhibitor, selectivity with respect to other NAD + -binding enzymes (e.g., other PARPs and oxidoreductases) is desirable but selectivity between the tankyrases is not.…”

mentioning

confidence: 99%

Design and Discovery of 2-Arylquinazolin-4-ones as Potent and Selective Inhibitors of Tankyrases

Nathubhai

Wood

Lloyd

et al. 2013

ACS Med. Chem. Lett.

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Tankyrases (TNKSs) are poly(ADP-ribose)polymerases (PARPs) that are overexpressed in several clinical cancers. They regulate elongation of telomeres, regulate the Wnt system, and are essential for the function of the mitotic spindle. A set of 2-arylquinazolin-4-ones has been designed and identified as potent and selective TNKS inhibitors, some being more potent and selective than the lead inhibitor XAV939, with IC 50 = 3 nM vs. TNKS-2. Methyl was preferred at the 8-position and modest bulk at the 4-position of the 2-phenyl group; electronic effects and H-bonding were irrelevant, but charge in the 4′-substituent must be avoided. Molecular modeling facilitated initial design of the compounds and rationalization of the SAR of binding into the nicotinamide-binding site of the target enzymes. These compounds have potential for further development into anticancer drugs.

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“…The TNKS inhibitor binds to two pockets: the nicotinamide pocket and the induced pocket (32). Nicotinamide pocket composing residues are conserved among the PARP family enzymes, including TNKS; thus, the nicotinamide pocket binders such as XAV939 show less selectivity to TNKS (16,33).…”

Section: Discussionmentioning

confidence: 99%

“…The natural ligand of TNKS is b-NAD is not present in the apo-TNKS structure (32,33). This induced pocket is created by the drastic rearrangement of Phe1188 and is suggested to enable the nicotinamide noncompetitive inhibition of TNKS (33).…”

Section: K-756 Binds To the Induced Pocket Of Tnks1mentioning

confidence: 99%

The Discovery and Characterization of K-756, a Novel Wnt/β-Catenin Pathway Inhibitor Targeting Tankyrase

Okada-Iwasaki

Takahashi

Watanabe

et al. 2016

Molecular Cancer Therapeutics

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The Wnt/b-catenin pathway is a well-known oncogenic pathway. Its suppression has long been considered as an important challenge in treating cancer patients. Among colon cancer patients in particular, most patients carry an adenomatous polyposis coli (APC) mutation that leads to an aberration of Wnt/b-catenin pathway. To discover the small molecule inhibitors of the Wnt/b-catenin pathway, we conducted highthroughput screening in APC-mutant colon cancer DLD-1 cells using a transcriptional reporter assay, which identified a selective Wnt/b-catenin pathway inhibitor, K-756. K-756 stabilizes Axin and reduces active b-catenin, and inhibits the genes downstream of endogenous Wnt/b-catenin. We subsequently identified that K-756 is a tankyrase (TNKS) inhibitor. TNKS, which belongs to the PARP family, poly-ADP ribosylates Axin and promotes Axin degradation via the proteasome pathway. K-756 binds to the induced pocket of TNKS and inhibits its enzyme activity. Moreover, PARP family enzyme assays showed that K-756 is a selective TNKS inhibitor. K-756 inhibited the cell growth of APC-mutant colorectal cancer COLO 320DM and SW403 cells by inhibiting the Wnt/b-catenin pathway. An in vivo study showed that the oral administration of K-756 inhibited the Wnt/b-catenin pathway in colon cancer xenografts in mice. To further explore the therapeutic potential of K-756, we also evaluated the effects of K-756 in non-small cell lung cancer cells. Although a single treatment of K-756 did not induce antiproliferative activity, when K-756 was combined with an EGFR inhibitor (gefitinib), it showed a strong synergistic effect. Therefore, K-756, a novel selective TNKS inhibitor, could be a leading compound in the development of anticancer agents. Mol Cancer Ther; 15(7); 1525-34. Ó2016 AACR.

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Structural Basis of Selective Inhibition of Human Tankyrases

Cited by 126 publications

References 33 publications

Evaluation and Structural Basis for the Inhibition of Tankyrases by PARP Inhibitors

Evaluation and Structural Basis for the Inhibition of Tankyrases by PARP Inhibitors

Design and Discovery of 2-Arylquinazolin-4-ones as Potent and Selective Inhibitors of Tankyrases

The Discovery and Characterization of K-756, a Novel Wnt/β-Catenin Pathway Inhibitor Targeting Tankyrase

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