zimlovisertib (PF-06650833)

As a result, inhibition of IRAK4 has been investigated as a means of attenuating a range of autoimmune diseases including rheumatoid arthritis, with zimlovisertib demonstrating encouraging results in a Phase 2 rheumatoid arthritis study. Using the knowledge gained in the development of R835, we have identified R851 as a second generation dual IRAK1 and IRAK4 inhibitor. The increased potency in whole blood assays is believed to be driven by a reduction in protein binding. We predict that R851 will require a significantly lower exposures for efficacy in humans which should position this molecule for a chronic condition like rheumatoid arthritis.

A few potent IRAK4 inhibitors such as PF-06650833, RA9 and BAY1834845 have recently entered phase I/II clinical trial studies. We designed few IRAK4 inhibitors based on these results, which possessed higher activity (predicted pIC) than the most active compounds of the dataset selected for this study. Moreover, ADMET properties of these inhibitors revealed promising results and need to be validated using experimental studies.

IL1RAP knockdown significantly reduced cell viability, invasiveness, and clonogenic growth in pancreatic cancer cell lines. Inhibition of the downstream interleukin-1 receptor-associated kinase 4 (IRAK4) using two pharmacologic inhibitors, CA-4948 and PF06650833, resulted in reduced growth in pancreatic cancer cell lines and in xenograft models.