Janus tyrosine kinase 3 (JAK3), a non-receptor protein tyrosine kinase, is one of the four family members of Janus kinase, the other three being JAK1, JAK2 and TYK2. Expressed in lymphoid cells and involved in the signaling of T cell functions, JAK3 have been identified in humans as a cause of severe combined immunodeficiency disease (SCID), which manifests as a depletion of T cell, B cell, and natural killer (NK) cells with no other defects. Consequently, selective JAK3 inhibition has been shown to be an attractive therapeutic strategy for autoimmune diseases such as rheumatoid arthritis (RA) Consequently, selective JAK3 inhibition has been shown to be an attractive therapeutic strategy for autoimmune diseases such as rheumatoid arthritis (RA) (and alopecia areata (AA)). Tofacitinib is the first oral Janus kinase inhibitor indicated for treatment of moderate to severe RA. Tofacitinib demonstrated efficacy and safety comparable to other disease-modifying antirheumatic drugs as indicated by achievement of the ACR20, ACR50 and ACR70 criteria defined by the American College of Rheumatology. 171 A high level of selectivity toward JAK3 is achieved by the covalent interaction of PF 06651600 (Ritlecitinib) with a non-conserved cysteine residue (Cys909) in the catalytic domain of JAK3, whose identity is a serine residue in the other JAK isoforms. In addition to its high selectivity, PF 06651600 also shows good oral bioavailability and favorable pharmacokinetic properties, making it an attractive drug candidate. It has been demonstrated to be effective for treatment of moderate-to-severe RA that does not respond to methotrexate. 174, 175 RB1, is a 4-aminopiperidine-based compound which is highly selective for JAK3 inhibition, with an IC50 of value of 40 nM. Reasonable pharmacokinetics properties, good oral availability, and favorable results of toxicology studies suggest that RB1 has the potential to be an efficacious treatment for RA and other immune-related diseases. The highly selective JAK3 inhibitor Z583 is a promising candidate with significant therapeutic potential for autoimmune diseases. Z583 is an attractive novel drug candidate for RA due to its potent efficacy and lack of side effects linked to systemic suppression making it worthy of further evaluation in clinical study. 169, 177