Preclinical Lead Optimization of a 1,2,4-Triazole Based Tankyrase Inhibitor.,Journal of Medicinal Chemistry

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Preclinical Lead Optimization of a 1,2,4-Triazole Based Tankyrase Inhibitor.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-06-08 , DOI: 10.1021/acs.jmedchem.0c00208
Jo Waaler _{1,

2} , Ruben G G Leenders ₃ , Sven T Sowa ₄ , Shoshy Alam Brinch _{1,

2} , Max Lycke _{1,

2} , Piotr Nieczypor ₃ , Sjoerd Aertssen ₃ , Sudarshan Murthy ₄ , Albert Galera-Prat ₄ , Eddy Damen ₃ , Anita Wegert ₃ , Marc Nazaré ₅ , Lari Lehtiö ₄ , Stefan Krauss _{1,

2}

Affiliation

Tankyrases 1 and 2 are central biotargets in the WNT/β-catenin signaling and Hippo signaling pathways. We have previously developed tankyrase inhibitors bearing a 1,2,4-triazole moiety and binding predominantly to the adenosine binding site of the tankyrase catalytic domain. Here we describe a systematic structure-guided lead optimization approach of these tankyrase inhibitors. The central 1,2,4-triazole template and trans-cyclobutyl linker of the lead compound 1 were left unchanged, while side-group East, West, and South moieties were altered by introducing different building blocks defined as point mutations. The systematic study provided a novel series of compounds reaching picomolar IC₅₀ inhibition in WNT/β-catenin signaling cellular reporter assay. The novel optimized lead 13 resolves previous atropisomerism, solubility, and Caco-2 efflux liabilities. 13 shows a favorable ADME profile, including improved Caco-2 permeability and oral bioavailability in mice, and exhibits antiproliferative efficacy in the colon cancer cell line COLO 320DM in vitro.

中文翻译：

基于1,2,4-三唑的Tankyrase抑制剂的临床前铅优化。

Tankyrases 1和2是WNT /β-catenin信号传导和Hippo信号传导途径中的主要生物靶标。我们先前已经开发了带有1,2,4-三唑部分并且主要结合到坦吉糖酶催化结构域的腺苷结合位点上的坦吉糖酶抑制剂。在这里，我们描述了这些坦科聚合酶抑制剂的系统结构指导的铅优化方法。铅化合物1的中心1,2,4-三唑模板和反式环丁基接头保持不变，而侧基East，West和South部分则通过引入定义为点突变的不同结构单元进行了改变。系统性研究提供了一系列在WNT /β中达到皮摩尔IC ₅₀抑制的化合物-连环蛋白信号传导细胞报道分子测定。新型优化的铅13解决了以前的阻转异构，溶解度和Caco-2外排负债问题。图13显示了有利的ADME概况，包括改善的Caco-2通透性和小鼠的口服生物利用度，并且在结肠癌细胞系COLO 320DM中具有抗增殖功效。

更新日期：2020-07-09

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