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From PARP1 to TNKS2 Inhibition: A Structure-Based Approach
Stefano Tomassi1, Julian Pfahler2, Nicola Mautone3
1Department of Pharmacy, University of Naples, "Federico II", 80131 Naples, Italy.
ACS Medicinal Chemistry Letters
|May 22, 2020
Summary
Researchers developed a novel bis-quinazolinone compound 5 that selectively inhibits tankyrase 2 (TNKS2). This potent inhibitor shows antiproliferative effects in colorectal cancer cells, targeting the Wnt/β-catenin pathway.
Area of Science:
- Medicinal Chemistry
- Oncology
- Structural Biology
Background:
- Tankyrases (TNKSs) are emerging therapeutic targets for solid tumors driven by the Wnt/β-catenin pathway.
- Previous work identified MC2050 as a micromolar inhibitor of PARP1.
Purpose of the Study:
- To rationally design potent and selective tankyrase inhibitors.
- To discover novel anticancer agents targeting the Wnt/β-catenin pathway.
Main Methods:
- X-ray crystallography of PARP1 complexed with MC2050.
- Computational analysis of structural differences between TNKS and PARP active sites.
- Structure-based drug design and synthesis of novel compounds.
Main Results:
- Discovery of bis-quinazolinone compound 5, a picomolar and selective TNKS2 inhibitor.
- Compound 5 demonstrated antiproliferative activity in DLD-1 colorectal cancer cells.
- The study established a structure-based rationale for TNKS inhibitor development.
Conclusions:
- Bis-quinazolinone 5 represents a promising lead compound for TNKS2-targeted cancer therapy.
- Targeting TNKS2 offers a viable strategy for inhibiting the Wnt/β-catenin pathway in cancer.
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