PF-06651600 is a newly discovered irreversible covalent JAK3-selective inhibitor. A high level of selectivity towards JAK3 is achieved by the covalent interaction of PF-06651600 with a unique cysteine residue (Cys-909) in the catalytic domain of JAK3, which is replaced by a serine residue in the other JAK isoforms. PF-06651600 allowed the comparison of JAK3-selective inhibition to pan-JAK or JAK1-selective inhibition, in relevant immune cells to a level that could not be achieved previously without such potency and selectivity. In vitro, PF-06651600 inhibits Th1 and Th17 cell differentiation and function, and in vivo it reduces disease pathology in rat adjuvant-induced arthritis as well as in mouse experimental autoimmune encephalomyelitis models. Preclinical data demonstrates that inhibition of the cytolytic function of CD8+ T cells and NK cells by PF-06651600 is driven by the inhibition of TEC kinases. Based on the underlying pathophysiology of inflammatory diseases such as rheumatoid arthritis, inflammatory bowel disease, alopecia areata and vitiligo, the dual activity of PF06651600 towards JAK3 and the TEC kinase family may provide a beneficial inhibitory profile for therapeutic intervention. PF-06651600 is in phase III clinical trial for the treatment of alopecia areata and in phase II clinical trial for the treatment of Crohn's disease, Rheumatoid arthritis, Ulcerative colitis and Vitiligo.

Momelotinib (CYT387) is an ATP-competitive small molecule that potently inhibits JAK1/JAK2 kinases. Momelotinib is developing by Gilead Sciences for the oral treatment of pancreatic and non-small cell lung cancers, and myeloproliferative disorders (including myelofibrosis, essential thrombocythaemia and polycythaemia vera).

Taurolidine [bis(1,1-dioxoperhydro-1,2,4-thiadiazinyl-4)-methane (TRD)], a product derived from the aminosulfoacid taurin, was first described as an anti-bacterial substance. Taurolidine is a small dimeric molecule with molecular weight 284. It comprises the semiconditional amino acid taurine. Taurolidine was originally designed as a broad-spectrum antibiotic. Taurolidine has a broad antimicrobial spectrum of activity that is effective against aerobes and anaerobes, Gram-negative and Gram-posi-tive bacteria as well as yeasts and moulds in vitro. Taurolidine is also effective against methicillin-resistant and vancomycin-resistant bacteria (MRSA, VISA and VRE). It was mainly used in the treatment of patients with peritonis as well as antiendoxic agent in patients with systematic inflammatory response syndrome. It has been shown to be an effective bactericidal agent against both aerobic and anaerobic bacteria. It is currently licensed for intraperitoneal use in several European countries for the treatment of peritonitis. The compound appears to be nontoxic and has an excellent safety record since its initial introduction over 30 years ago. Taurolidine also possesses antiadherence properties and has been shown in vivo to reduce the extent and severity of postoperative peritoneal adhesions. It also possesses a strong anti-inflammatory action. This action appears, at least in part, to arise through its ability to inactivate endotoxin. Inflammation-induced tumor development is well described in the literature. Taurolidine’s anti-inflammatory and antiadherence properties prompted an investigation to examine whether it has a role in antitumor therapy. Taurolidine induces cancer cell death through a variety of mechanisms. It appears to act through enhancing apoptosis, inhibiting angiogenesis and tumor adherence, downregulating proinflammatory cytokine and endotoxin levels, and stimulating the immune system in response to surgically induced trauma. Taurolidine is currently in preclinical development for neuroblastoma. In February 23, 2018 the U.S. Food and Drug Administration (FDA) granted orphan drug designation to taurolidine for the treatment of neuroblastoma. Taurolidine is a key component in the Neutrolin®, a novel anti-infective solution for the reduction and prevention of catheter-related infections and thrombosis in patients requiring central venous cathers in end stage renal disease. Neutrolin contains a mix of Taurolidine, Citrate and Heparin. Neutrolin is designed to: 1) Aid in the prevention of Catheter-Related Bloodstream Infections (CRBIs) and 2) Prevent catheter dysfunction (due to blood clotting).

Daprodustat (GSK1278863) is a low nanomolar hypoxia-inducible factor (HIF) prolyl hydroxylase (PHD) inhibitor, that increases HIF stability and action. In preclinical studies, Daprodustat stabilizes HIFα in cell lines, resulting in the production of increased levels of erythropoietin (EPO). In normal mice, a single dose of Daprodustat induced significant increases in circulating plasma EPO but only minimal increases in plasma vascular endothelial growth factor (VEGF-A) concentrations. Daprodustat significantly increased reticulocytes and red cell mass parameters in pre-clinical species following once-daily oral administration and has demonstrated an acceptable nonclinical toxicity profile supporting continued clinical development. In a phase 1 study, Daprodustat was well tolerated and increased erythropoietin (EPO) levels in apparently healthy individuals proportional to dose. In phase 2a studies in non–dialysis-dependent chronic kidney disease (NDD CKD) and end-stage renal disease Daprodustat 4-10 mg once-daily produced the dose-dependent increase in hemoglobin relative to placebo. The Phase III programme for the drug includes two studies evaluating its safety and efficacy compared to recombinant human erythropoietin in dialysis-dependent subjects with anemia associated with CKD (ASCEND-D) and in non-dialysis dependent patients with the condition (ASCEND-ND).