Preclinical Lead Optimization of a 1,2,4-Triazole Based Tankyrase Inhibitor

Abstract

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 <i>trans-</i>cyclobutyl linker of the lead compound <b>1</b> 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<i>-</i>catenin signaling cellular reporter assay. The novel optimized lead <b>13</b> resolves previous atropisomerism, solubility, and Caco-2 efflux liabilities. <b>13</b> 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 <i>in vitro.</i>