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Discovery of Novel Spiroindoline Derivatives as Selective Tankyrase Inhibitors

Fumiyuki Shirai, Takeshi Tsumura, Yoko Yashiroda

  • 1RIKEN Program for Drug Discovery and Medical Technology Platforms , 2-1 Hirosawa , Wako , Saitama 351-0198 , Japan.

Journal of Medicinal Chemistry
|March 19, 2019
PubMed

Insights

We identified RK-287107, a potent tankyrase inhibitor, which reduces Wnt/β-catenin signaling. This compound effectively inhibited colorectal cancer cell proliferation and tumor growth in mice, showing promise as an anticancer agent.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • The WNT pathway is crucial in cancer development.
  • Tankyrases (TNKS/TNKS2) regulate WNT signaling by controlling AXIN degradation.
  • Inhibiting TNKS/TNKS2 can reduce WNT/β-catenin signaling, offering a potential cancer treatment strategy.

Purpose of the Study:

  • To discover small-molecule inhibitors of TNKS/TNKS2 with drug-like properties.
  • To investigate the effects of tankyrase inhibition on tumor growth.
  • To evaluate RK-287107 as a potential anticancer therapeutic.

Main Methods:

  • High-throughput screening to identify initial hits.
  • Medicinal chemistry optimization leading to RK-287107 (40c).
  • In vitro assays measuring TNKS/TNKS2 inhibition, WNT-responsive TCF reporter activity, and cancer cell proliferation.
  • In vivo studies using a mouse xenograft model to assess tumor growth inhibition.

Main Results:

  • RK-287107 is a potent TNKS/TNKS2 inhibitor with high selectivity over PARP1 (>7000-fold).
  • RK-287107 effectively inhibited WNT-responsive TCF reporter activity and proliferation of COLO-320DM colorectal cancer cells.
  • RK-287107 demonstrated dose-dependent tumor growth inhibition in a mouse xenograft model.

Conclusions:

  • RK-287107 is a promising lead compound for developing novel tankyrase inhibitors.
  • Targeting TNKS/TNKS2 with RK-287107 represents a viable strategy for anticancer therapy.
  • Further development of RK-287107 could lead to new treatments for WNT-driven cancers.

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