Chitinase-3-like protein 1 (CHI3L1, YKL-40) is a carbohydrate-binding protein that unlike other members of 18-glycosylhydrolase family, including chitotriosidase (CHIT1) and acidic mammalian chitinase (AMCase) does not possess chitinase activity. YKL-40 has been shown to bind short chitin oligomers and it has been suggested to bind heparin. Elevated serum YKL-40 level has been correlated with poor prognosis and shorter survival of patients with cancer. The protein has been proposed to act through IL13Ra2 and Syndecan-1 receptors via respectively chitin-binding and heparin-binding domains but its detailed biological functions are still poorly understood. Herein, we demonstrate carbohydrate-binding properties of YKL-40, chitooligosaccharides binding, heparins/heparan sulphates binding, and the interplay between both types of these interactions. In this regard, we also present the screening cascade of small molecule compounds capable of interfering with YKL-40 binding chitooligosaccharide ligands alone (compound 1) or chitooligosaccharide and heparin / heparan sulphate ligands (compound 2) concurrently. Low nanomolar activities have been identified among both groups of compounds. Parallel optimization of ADME and pharmacokinetic properties of compounds is underway. Similarly, in vitro cellular assays, as well as in vivo models to study compounds’ anti-cancer effects are under development.

Discovery of small molecule compounds interfering with YKL-40 carbohydrate binding as potential therapeutics for cancer

2019 Fall National Meeting

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