The Use of Structural Biology in Janus Kinase Targeted Drug Discovery

Title: The Use of Structural Biology in Janus Kinase Targeted Drug Discovery

Volume: 12 Issue: 4

Author(s): Nilda L. Alicea-Velazquez and Titus J. Boggon

Affiliation:

Keywords: Jak kinase, crystal structure, CP-690, 550, Jak2-V617F, kinase inhibitor, drug, cytokine signaling, mutation, translocation, STAT

Abstract: The Janus kinases (or Jak kinases) mediate cytokine and growth factor signal transduction. Acquired or inherited Jak mutations can result in dysregulation of Jak-mediated signal transduction and can be critical to disease acquisition in neoplasias including acute myeloid, acute lymphoblastic and acute megakaryoblastic leukemias, and in rare X-linked severe combined immunodeficiency. The discovery of an acquired Jak2 point mutation, V617F, in significant numbers of patients with classical myeloproliferative disorders has increased the interest in development of Jak2-specific tyrosine kinase inhibitors and consequently there are now over 20 publically available structures of Jak kinase domains that describe all four family members, Jak1, Jak2, Jak3, and Tyk2. Here we review the recent advances in understanding the druggable structure and function of the Jak family, with a focus on the structural biology of the Jak kinase domain. We will discuss how these advances impact the development of Jak-targeted therapeutics.

Cite this article as:

L. Alicea-Velazquez Nilda and J. Boggon Titus, The Use of Structural Biology in Janus Kinase Targeted Drug Discovery, Current Drug Targets 2011; 12 (4) . https://dx.doi.org/10.2174/138945011794751528