Reference Detail

Request Content

Contact

Missing content? – Request curation!

Request curation for specific Genes, Variants, or PubMed publications.

Have questions, comments, or suggestions? - Let us know!

Email us at : ckbsupport@genomenon.com

Ref Type Journal Article
PMID (35849876)
Authors Kim DY, Kwon YJ, Seo WY, Kim UI, Ahn S, Choi SM, Bang HT, Kim K, Kim JS
Title Tankyrase-selective inhibitor STP1002 shows preclinical antitumour efficacy without on-target toxicity in the gastrointestinal tract.
Journal Vol Issue Date Pages Journal Short Title
European journal of cancer (Oxford, England : 1990) 173 2022 Jul 15 41-51 Eur J Cancer
URL
Abstract Text Tankyrase inhibition stabilises AXINs and antagonises the Wnt/β-catenin pathway in adenomatous polyposis coli (APC)-mutated colorectal cancer (CRC), suggesting that tankyrase is a potential therapeutic target for APC-mutated CRC. However, clinical trials on reported tankyrase inhibitors have been severely limited by on-target toxicity in the gastrointestinal (GI) tract. Herein, we report a new tankyrase-selective inhibitor, STP1002, having preclinical antitumour efficacy without on-target toxicity in APC-mutated CRC models.STP1002 was developed and characterised using in vitro and in vivo functional studies; its pharmacokinetics, antitumour efficacy and toxicity were evaluated in vivo.STP1002 showed potent, selective inhibition of tankyrase 1/2 but not of members of the poly (ADP-ribose) polymerase 1/2 (PARP1/2). STP1002 exerted antitumour activity by stabilising AXINs and antagonising the Wnt/β-catenin pathway in a subset of APC-mutated CRC cell lines but not in inhibitor-resistant cells and APC-wild-type CRC cell lines. STP1002 showed favourable pharmacokinetic profiles for oral administration once daily. STP1002 inhibited tumour growth of APC-mutated CRC xenograft animal models but not of APC-wild type models in a dose-dependent manner. The antitumour efficacy of STP1002 was confirmed using APC-mutated CRC patient-derived tumour xenograft models. STP1002 showed no significant on-target toxicity in the GI tract compared to G007-LK, which shows severe ileum toxicity in preclinical animal models.These results demonstrate that STP1002, a novel, orally active tankyrase inhibitor, shows preclinical antitumour efficacy without on-target toxicity in the GI tract. Our data provide a rationale for a clinical trial on STP1002 as a potential tankyrase-targeted drug in patients with APC-mutated CRC.

Filtering

  • Case insensitive filtering will display rows if any text in any cell matches the filter term
  • Use simple literal full or partial string matches
  • Separate multiple filter terms with a space. Any order may be used (i. e. a b c and c b a are equivalent )
  • Filtering will only apply to rows that are already loaded on the page. Filtering has no impact on query parameters.
  • Use quotes to match on a longer phrase with spaces (i.e. "mtor c1483f")

Sorting

  • Generally, the default sort order for tables is set to be first column ascending; however, specific tables may set a different default sort order.
  • Click on any column header arrows to sort by that column
  • Hold down the Shift key and click multiple columns to sort by more than one column. Be sure to set ascending or descending order for a given column before moving on to the next column.