The synthesis of 1,2,3-triazoles as binders of D-dopachrome tautomerase (D-DT) for the development of dual-targeting inhibitors

Despite recent advances in the treatment of cancer, the issue of therapy resistance remains one of the most significant challenges in the field. In this context, signaling molecules, such as cytokines have emerged as promising targets for drug discovery. Examples of cytokines include macrophage migration inhibitory factor (MIF) and its closely related analogue D-dopachrome tautomerase (D-DT). In this study we aim to develop a new chemical class of D-DT binders and subsequently create a dual-targeted inhibitor that can potentially trigger D-DT degradation via the Proteolysis Targeting Chimera (PROTAC) technology. Here we describe the synthesis of a novel library of 1,2,3-triazoles targeting D-DT. The most potent derivative 19c (IC50 of 0.5 ± 0.04 μM with high selectivity toward D-DT) was attached to a cereblon (CRBN) ligand through aliphatic amides, which were synthesized by a remarkably convenient and effective solvent-free reaction. Enzyme inhibition experiments led to the discovery of the compound 10d, which exhibited moderate inhibitory potency (IC50 of 5.9 ± 0.7 μM), but unfortunately demonstrated no activity in D-DT degradation experiments. In conclusion, this study offers valuable insight into the SAR of D-DT inhibition, paving the way for the development of novel molecules as tools to study D-DT functions in tumor proliferation and, ultimately, new therapeutics for cancer treatment. [Display omitted] •Multifunctional biological targets require more sophisticated tools than merely downregulation or inhibition.•A first example of a non-competitive D-DT inhibitor with low micromolar activity has been synthesized.•A solvent-free ring-opening reaction of cyclic anhydrides was employed for the derivatization of pomalidomide.•A three-step click chemistry-based synthesis protocol was developed for the construction of dual inhibitors.•The synthesized D-DT-CRBN dual inhibitor was unable to act as a PROTAC.