Chitinases are chitin-degrading enzymes that belong to the glycosyl hydrolase family. It includes enzymatically active chitinases and chitinase-like proteins without enzymatic activity. Mammals have two distinct genes encoding for chitinase enzymes, chitotriosidase (CHIT1) and acidic mammalian chitinase (CHIA, hereafter referred to as AMCase). Both enzymes modulate inflammatory response in chitin-dependent and -independent manner. While AMCase is mostly produced at sites of Th2 inflammation and modulates allergic response in animal models of asthma, CHIT1 is the main chitinase produced by tissue-activated macrophages and expressed in human lung and liver. Moreover, CHIT1 modulates TGFβ and IL-13 signaling pathways to promote fibrotic response in animal models of pulmonary fibrosis. In this study, OATD-01 is a highly potent, orally active, and selective chitinase inhibitor with low nanomolar activity toward CHIT1 (hCHIT1, IC₅₀=23 nM). OATD-01 shows an excellent PK profile in multiple species. It is selectivity against a panel of other off-targets.

OATD-01 is a first-in-class chitinase inhibitor and has the potential for the research of idiopathic pulmonary fibrosis (IPF).

OATD-01 exhibits high affinity toward h/mCHIT1 and h/mAMCase. The K_i for all four enzymes are 17.3 nM, 26.05 nM, 4.8 nM and 5.7 nM, respectively. These K_i values reveals good correlation with earlier established IC₅₀ data. The IC₅₀ values are 23 nM, 28 nM, 9 nM and 7.8 nM for hCHIT1,mCHIT1, hAMCase and mAMCase, respectively. In addition, OATD-01 shows significant antifibrotic efficacy in an animal model of bleomycin-induced pulmonary fibrosis. Moreover, it reduces the degree of lung fibrosis in a dose-dependent manner, ultimately achieving comparable therapeutic efficacy to reference treatment with Nintedanib in this animal model.

In summary, OATD-01 is a highly active CHIT1 inhibitor. It has both an excellent PK profile in multiple species and selectivity against a panel of other off-targets. It also shows significant antifibrotic efficacy in an animal model of bleomycin-induced pulmonary fibrosis. OATD-01 is the first-in-class CHIT1 inhibitor and has a potential for the research of IPF.

Reference:

Robert Koralewski, et al. J Med Chem. 2020 Dec 24;63(24):15527-15540.