Bruton’s tyrosine kinase (BTK) is an enzyme encoded by the BTK gene in human. BTK is critical for the survival of B-cell neoplasms. BTK plays a crucial role in B cell development, differentiation, and signaling. Inhibition of BTK kinase activity is an important and practical way of treating Non-Hodgkin’s lymphoma (NHL). Proteolysis-targeting chimera (PROTAC) molecules are small molecules capable of bringing a target protein into the proximity of an E3 ligase of interest, causing consequent degradation of the target protein. PROTAC has emerged as a potent chemical approach for the selective degradation of cellular proteins.

Researchers have synthesized a new series of PROTACs targeting BTK, such as MT802. MT802 potently induces degradation of both wild-type and C481S mutant BTK in immortalized cells and patient-derived B-lymphocytes. However, the pharmacokinetic properties of MT802 were not suitable for further in vivo development. Therefore, researchers undertook a systematic medicinal chemistry campaign to overcome this issue. This approach results in the discovery of SJF620. SJF620 is a potent PROTAC BTK degrader with a significantly better pharmacokinetic profile than MT802. The PROTAC molecules should bind both BTK and E3 ligase through the corresponding targeting arm and degradation arm, respectively.

As a result, SJF620 is a promising compound for further exploration of BTK degradation in vivo. SJF620 contains a Lenalidomide analog for recruiting CRBN. Typically, the utilized degradation machinery is the ubiquitin–proteasome system (UPS) that recruits an E3 ubiquitin ligase followed by ubiquitination of the target protein and its subsequent degradation by the proteasome. Therefore, SJF620 may hold promise for further in vivo exploration of BTK degradation.

Saul Jaime-Figueroa, et al. Design, synthesis and biological evaluation of Proteolysis Targeting Chimeras (PROTACs) as a BTK degraders with improved pharmacokinetic properties. Bioorg Med Chem Lett. 2020 Feb 1;30(3):126877.