Tankyrase 1 Inhibitors with Drug-like Properties Identified by Screening a DNA-Encoded Chemical Library

Abstract

We describe the synthesis and screening of a DNA-encoded chemical library containing 76230 compounds. In this library, sets of amines and carboxylic acids are directly linked producing encoded compounds with compact structures and drug-like properties. Affinity screening of this library yielded inhibitors of the potential pharmaceutical target tankyrase 1, a poly(ADP-ribose) polymerase. These compounds have drug-like characteristics, and the most potent hit compound (X066/Y469) inhibited tankyrase 1 with an IC50 value of 250 nM.

DNA Encoded Libraries: A Visitor's Guide

“…DEL successes are not limited to the pharmaceutical industry, on-the-contrary, several academic labs have harnessed DEL to elucidate new binding molecules for various target proteins. [49][50][51][52][53] As an example, the group of Prof. Robert Lefkowitz at Duke University screened DNA encoded smallmolecule libraries containing 190 million compounds against purified human β2-adrenergic receptor (β2AR, Figure 4C). [54,55] This screening campaign afforded the discovery of a small molecule which exhibits a unique chemotype and low micromolar affinity for the target.…”

Molecular design opportunities presented by solvent‐exposed regions of target proteins

“…In recent years, DELs have attracted considerable attention as an effective approach for the discovery of new chemical equity for drug targets . With the increased application of DEL in drug discovery, many new compounds are emerging in the medicinal chemistry literature, as exemplified by receptor interacting protein 1 kinase inhibitor 203 and tankyrase 1 inhibitor 204 with drug‐like properties (Figure ) . A key factor for the success of the DNA‐encoded chemistry is the chemical diversity of the libraries, which enables the deep exploration of chemical spaces, being significantly superior to traditional high‐throughput screening (HTS) approaches .…”

“…3.1 | To design (PROTACs) by exploiting the solvent-exposed region Targeted protein degradation, using heterobifunctional small molecules (PROTACs) to remove protein targets from within cells, has emerged as a novel strategy for drug development, with the opportunity of providing therapeutic interventions not achievable with existing occupancy-based enzyme inhibition approaches. [156][157][158][159][160][161] Small-molecularweight synthetic PROTACs (185)(186)(187)(188)(189) have been used to selectively degrade various specific proteins (Figure 26), including pirin, 162 sirt2, 163 BET protein, 164 androgen receptor, 165 and BRD4 protein. 166 PROTACs consist of a targeting ligand (warhead) for the specific protein to be degraded, an E3 ubiquitin ligase recruitment binder, and a suitable linker connecting the two binders ( Figure 27).…”

“…183 With the increased application of DEL in drug discovery, many new compounds are emerging in the medicinal chemistry literature, as exemplified by receptor interacting protein 1 kinase inhibitor 203 and tankyrase 1 inhibitor 204 with drug-like properties ( Figure 31). 184,185 A key factor for the success of the DNA-encoded chemistry is the chemical diversity of the libraries, which enables the deep exploration of chemical spaces, being significantly superior to traditional highthroughput screening (HTS) approaches. 186 Another key factor for the success of the technology is that the conjugated DNA tags should be attached to a solvent-exposed region of the core scaffold (the positions that the DNA tags were attached was shown in Figure 30).…”

Regulation of Wnt/β‐catenin signalling by tankyrase‐dependent poly(ADP‐ribosyl)ation and scaffolding

“…The first potent toolbox TNKSi, XAV939 (Huang et al, ), IWR‐1 and IWR‐2 (Chen et al, ; Gunaydin et al, ), were discovered in phenotypic screens designed to identify antagonists of the Wnt/β‐catenin pathway, as were the inhibitors JW74 (Waaler et al, ), JW55 (Waaler et al, ), WIKI4 (James et al, ) and K‐756 (Okada‐Iwasaki et al, ). Numerous additional inhibitors were established through diverse approaches (see Zhan et al, ), including screening for compounds that rescue tankyrase‐induced lethality of yeast cells (Yashiroda et al, ) or induce a mitotic spindle defect (Johannes et al, ), fragment screening (Larsson et al, ; de Vicente et al, ), proteomics (Thomson et al, ), in silico screening or substructure searching, followed by compound optimization (Bregman et al, ; Elliott et al, ), screening of a DNA‐encoded library (Samain et al, ) and extensive structure–activity relationship studies, assisted by the structural analysis of tankyrase/PARP:inhibitor complexes (Hua et al, ; Shultz et al, ; Voronkov et al, ; Narwal et al, ; Liscio et al, ; Qiu et al, ; Haikarainen et al, ; Kumpan et al, ; Nkizinkiko et al, ; Paine et al, ; Haikarainen et al, ; Thomson et al, ). Numerous more drug‐like molecules, with optimized pharmacological properties, are now available, for example, G007‐LK (Lau et al, ; Voronkov et al, ) and NVP‐TNKS656 (Shultz et al, ).…”