Nerviano Medical Sciences researchers report the discovery, structure guided design, synthesis and biological evaluation of a novel class of JAK2 inhibitors on the journal Bioorganic & Medicinal Chemistry (“Pyrrole-3-carboxamides as potent and selective JAK2 inhibitors”; Brasca, MG, et al, Bioorg Med Chem. 2014 Sep 1; 22(17):4998-5012).
JAK2 is a member of the Janus kinase (JAK) family of intracellular tyrosine kinases which mediate cytokine-dependent signalling pathways and are involved in several human diseases, including cancer.
The compounds discovered by Nerviano Medical Sciences are potent inhibitors of the JAK2 kinase acitivity, displaying selectivity versus the other JAK family members. Optimization led to the identification of the orally available compound NMS-P953 with antitumor activity when tested in the JAK2-driven SET2 xenograft model.
The favourable pharmacokinetic and safety profile of NMS-P953 opens up the possibility for efficacy in JAK2-dependent diseases with limited side effects which may derive from inhibition of the other JAK family members.