Are Two Better Than One in Rheumatoid Arthritis? Development of Dual p38α MAPK/PDE-4 Inhibitors for Treatment of TNFα-Driven Diseases

Selective p38 mitogen-activated protein kinase (MAPK) inhibition has failed as a molecular principle in several phase II studies in rheumatoid arthritis, perhaps due to high redundancy with several bypass mechanisms (e.g., via c-Jun N-terminal kinases) in the kinome signaling involved in the release of tumor necrosis factor alpha (TNFα). We investigated compounds covering several MAPKs and selected a candidate based on its efficacy to inhibit TNFα release from human whole blood. Subsequently, we extended compound profiling to all ATP-like structures that bind to enzymes and receptors and thereby identified the dual p38α MAPK/phosphodiesterase 4 (PDE-4) inhibition as a mechanism to inhibit TNFα levels. Data from in vitro, ex vivo, and in vivo as well as phase I studies of the candidate CBS-3595 indicate that inhibition of both p38α MAPK and PDE-4 synergistically optimizes the antiinflammatory response.