Examination of the Impact of Triazole Position within Linkers on Solubility and Lipophilicity of a CDK9 Degrader Series

Abstract

Optimization of degrader properties is often a challenge due to their beyond-rule-of-5 nature. Given the paucity of known E3 ligases and the often-limited choice of ligands with varied chemical structures for a given protein target, degrader linkers represent the best position within the chimeric molecules to modify their overall physicochemical properties. In this work, a series of AT7519-based CDK9 degraders was assembled using click chemistry, facilitating the tuning of aqueous solubility and lipophilicity while retaining their linker type and molecular weight. Using chromatographic logD and kinetic solubility experiments, we show that degraders with similar chemical constitution but varied position of the embedded triazole demonstrate different lipophilicity and aqueous solubility properties. Overall, this work highlights the impact of triazole placement on linker composition through application of click chemistry for degrader synthesis and its ability to be used to promote the achievement of favorable physicochemical properties.

Click Chemistry and Targeted Degradation: A Winning Combination for Medicinal Chemists?

“…PROTAC permeability seems to be an important factor, but not crucial to create a ternary complex and induce POI degradation. Nevertheless, this research has showed that slight differences in the structure and the use of click chemistry may help in improving drug‐likeness of novel degraders, already at the early stage [63] …”

“…[61,62] Fuchs and coworkers decided to examine the impact of triazole position within various linker on physicochemical and biological properties of novel CDK9 degraders. [63] Pan-CDK9 inhibitor AT7519 was selected as the POI ligand [64] and thalidomide as the E3 ligase binder. The series of ten PROTACs containing triazole-alkyl linkers of different length (13-22, Figure 7) were synthetized using CuAAC reaction (CuSO 4 , sodium ascorbate, THF/water, RT, above 20 h) with yields ranging from 18 to 100 %.…”

“…Nevertheless, this research has showed that slight differences in the structure and the use of click chemistry may help in improving drug-likeness of novel degraders, already at the early stage. [63] Thanks to its effectiveness, the Wurz's strategy [59] was applied in the synthesis of PROTACs targeting glycogen synthase kinase 3 (GSK-3β) for the treatment of Alzheimer's disease (AD). To explore the potential degraders, the well- known GSK-3β inhibitor AZD2858 was used.…”

“…Fuchs and coworkers decided to examine the impact of triazole position within various linker on physicochemical and biological properties of novel CDK9 degraders [63] . Pan‐CDK9 inhibitor AT7519 was selected as the POI ligand [64] and thalidomide as the E3 ligase binder.…”

Utilising the intrinsic fluorescence of pomalidomide for imaging applications

“…16 The resulting pomalidomide-linkers were BOC deprotected with TFA, and then reacted with an activated pentafluorophenyl (Pfp) ester of JQ1 ( 3 ) which gave conjugates 4a–j . 28 To gain additional diversity of linkers, 29 a copper( i )-catalyed azide–alkyne cycloaddition reaction was used, 30 which connected JQ1-PEG-azide linkers ( 6a–c ) with propargylated pomalidomide ( 5 ) to afford conjugates 7a–c .…”