Discovery of Potent and Highly Selective Interleukin-2-Inducible T-Cell Kinase Degraders with In Vivo Activity.

Abstract

Interleukin-2-inducible T-cell kinase (ITK) is a promising therapeutic target for human autoimmune diseases and T-cell malignant lymphomas. This paper reports the development of a series of cereblon-recruiting ITK proteolysis targeting chimeras based on a structure-based design strategy. The representative compounds 23 and 28 exhibited potent ITK degradation and IL-2 inhibition activities in Jurkat cells. Global proteomic profiling assays indicated that compounds 23 and 28 are highly selective ITK degraders. Moreover, compound 28 showed good plasma exposure levels and elicited efficient, rapid, and prolonged ITK degradation in Balb/c mice. Furthermore, it significantly suppressed IL-2 secretion stimulated by anti-CD3 antibody. Compound 28 represents the first effective and highly selective ITK degrader. Thus, 28 is a valuable tool compound for further in vitro and in vivo studies exploring the underlying biological effects and potential therapeutic utility of ITK degradation in human diseases.