Second‐Generation CD73 Inhibitors Based on a 4,6‐Biaryl‐2‐thiopyridine Scaffold

Abstract

Various series of 4,6‐biaryl‐2‐thiopyridine derivatives were synthesized and evaluated as potential ecto‐5′‐nucleotidase (CD73) inhibitors. Two synthetic routes were explored and the coupling of 4,6‐disubstituted 3‐cyano‐2‐chloro‐pyridines with selected thiols allowed us to explore the structural diversity. Somehow divergent results were obtained in biological assays on CD73 inhibition using either the purified recombinant protein or cell‐based assays, highlighting the difficulty to target protein‐protein interface on proteins existing as soluble and membrane‐bound forms. Among the 18 new derivatives obtained, three derivatives incorporating morpholino substituents on the 4,6‐biaryl‐2‐thiopyridine core were shown to be able to reverse the adenosine‐mediated immune suppression on human T cells. The higher blockade efficiency was observed for 2‐((3‐cyano‐4,6‐bis(4‐morpholinophenyl)pyridin‐2‐yl)thio)‐N‐(isoxazol‐3‐yl)acetamide (with total reversion at 100 μM) and methyl 2‐((3‐cyano‐4,6‐bis(4‐morpholinophenyl)pyridin‐2‐yl)thio)acetate (with partial reversion at 10 μM). Thus, this series of compounds illustrates a new chemotype of CD73 allosteric inhibitors.

Discovery of Novel Non-Nucleoside Inhibitors Interacting with Dizinc Ions of CD73

“…A solution of 20 (1.00 g, 2.30 mmol) in 10 mL of DCM/CH 3 OH = 1:1 (DCM/CH 3 OH = 1:1, V/V) was treated with 10% Pd/C (10 wt %) and hydrogenated for 12 h. The catalyst was filtered off through Celite, and the filtrate was concentrated to give the title compound 21 as a brown oil (0.89 g) in a 95% yield, which was directly used for the next reaction without further purification. 1 (22). Compound 16 (5 g, 26.16 mmol), sodium chlorite (21.29 g, 235.42 mmol), sodium dihydrogen phosphate (28.24 g, 235.42 mmol), and 2-methyl-2-butene (45 mL) were taken in a reaction flask, 60 mL of tert-butanol and 20 mL of THF were added, and the product was stirred overnight at room temperature, then extracted with 1 N HCl to pH = 2−3, extracted with EA and spun dry, then pulped with 50 mL of EA and filtered to obtain a yellow solid 22, and the product did not need further purification.…”

“…Among them, benzotriazole analogue 7b cocrystallized with CD73 in the closed conformation exhibits a competitive binding mode. 21 In addition, the noncompetitive inhibitor LY-3475070 (8) 4 and allosteric inhibitor 9 22 also showed good prospects.…”

The Clinical Significance of CD73 in Cancer

“…This allowed targeted modifications of the nucleobase, sugar, and zinc-binding groups and led to the development of many highly effective and promising inhibitors [100]. All of the originating compounds are so-called nucleotide-based smallmolecule and competitive inhibitors, since they directly bind to the catalytic site [101]. One promising candidate is AB680, a highly potent and selective CD73 inhibitor with improved metabolic stability [97].…”

“…The most promising chemical structural families for the development of this kind of inhibitors are sulphonamides, anthraquinones, and other flavonoids [105]. In order to improve the specificity, allosteric binding small-molecule inhibitors are of interest [101]. In this context, the dimerization interface of CD73 has been reported to be a promising target site [106].Many monoclonal antibodies targeting CD73 have been developed and proven to cause anti-cancer effects in preclinical experiments [107][108][109].…”

Nucleophilic C4-selective (hetero) arylation of pyridines for facile synthesis of heterobiaryls

“…Pyridine, a prominent component in the realms of agrochemicals, pharmaceuticals, and functional materials (Vitaku et al, 2014;Zhong, et al, 2014), is often a key constituent of N-heterobiaryl scaffolds due to their rigid and adaptable three-dimensional structures (Wu and Chan, 2006;Ghoteimi et al, 2023;Yang et al, 2016;Lee, H. et al, 2019;Jo, W. et al, 2020;Li, H. et al, 2021;Shao et al, 2021;Nguyen, N. H. et al, 2022;Takahashi, F., and Yorimitsu, H., 2023). These structures are frequently used in the fabrication of therapeutic agents or as ligands for metal catalyst complexes.…”