Development of piperidinyl dipyrrrolopyridine-based dual inhibitors of Janus kinase and Bruton's tyrosine kinase: a potential therapeutic probability to deal with rheumatoid arthritis

Rheumatoid arthritis is an autoimmune disorder causing joint deformity and work disability. Several drugs are available to deal with the disease including conventional drugs; biological drugs such as TNFα inhibitors, B cell-targeted drugs, T cell co-stimulation inhibitors, interleukin-6 inhibitors, and interleukin-1 inhibitors; and kinase inhibitory drugs. In spite of the broad spectrum of drugs available, the disease remains uncontrolled in a number of patients and there is a need for new drugs with better efficacy and universal response rate. The failure of the available drugs to control the disease can be owed to the complex pathogenesis with complementary pathways of disease progression. The blockade of one pathway cannot supersede pathogenesis through other complementary pathways. Janus kinase (JAK) and Bruton's tyrosine kinase (BTK) are the two important mediators of disease which control a number of signaling pathways involved in rheumatoid arthritis pathogenesis. In this study, using the computer-aided drug designing techniques (virtual screening, molecular docking, and molecular dynamics studies), we have designed piperidinyl dipyrrolopyridine-based dual inhibitors of Janus kinase and Bruton's tyrosine kinase. Dual JAK and BTK inhibitors seem promising to fight the complex pathogenesis of the disease at multiple fronts and can be the future drug for patients unresponsive to current remedies.

Keywords: Bruton’s tyrosine kinase; Dual inhibition; Janus kinase; Molecular docking; Molecular dynamic simulations; Rheumatoid arthritis.