Discovery of Potent and Highly Selective Thienopyridine Janus Kinase 2 Inhibitors

Abstract

Developing Janus kinase 2 (Jak2) inhibitors has become a significant focus for small molecule drug discovery programs in recent years due to the identification of a Jak2 gain-of-function mutation in the majority of patients with myeloproliferative disorders (MPD). Here, we describe the discovery of a thienopyridine series of Jak2 inhibitors that culminates with compounds showing 100- to >500-fold selectivity over the related Jak family kinases in enzyme assays. Selectivity for Jak2 was also observed in TEL-Jak cellular assays, as well as in cytokine-stimulated peripheral blood mononuclear cell (PBMC) and whole blood assays. X-ray cocrystal structures of 8 and 19 bound to the Jak2 kinase domain aided structure-activity relationship efforts and, along with a previously reported small molecule X-ray cocrystal structure of the Jak1 kinase domain, provided structural rationale for the observed high levels of Jak2 selectivity.

Triazolopyridines as Selective JAK1 Inhibitors: From Hit Identification to GLPG0634

“…Consequently, neither a K i nor an IC 50 measurement at ATP Km in an enzymatic assay represents a good evaluation of cellular activity for ATP competitive inhibitors. 23,24,25 Consequently, to assess the profile of compound 65 in potentially more relevant cellular settings, its potency and selectivity was determined in cellular and whole blood assays. In recent years the importance of the JAKs in the heterodimeric pair has been the source of intensive research.…”

Selective JAK Inhibitors

“…JAK3 inhibition has immunosuppressive effects. Amgen (Thousand Oaks, CA) reported a series of thienopyridine compounds as selective and potent JAK2 inhibitors [31]. Compound 14 was the most potent JAK2 inhibitor with the highest selectivity over the other JAK family kinases.…”

Selective JAK1 inhibitor and selective Tyk2 inhibitor patents

“…The key to achieving selectivity appears to be the nature of the aryl or heteroaryl group attached to the pyrrolidine nitrogen in structures of the form (19). That this can result in highly selective agents is illustrated by the compounds (20) and (21), the most selective shown of each of the two subsets of compounds, respectively, 132.5-and 53.3-fold selective for JAK1 relative to JAK2. However, the nicotinonitrile derivative (22) is the clearly preferred compound (Figure 4).…”

“…This has led to diverse chemotypes being identified as providing selectivity for these kinases. JAK2 selective inhibitors have been identified by Rigel (R-723) [15], Ambit (AC-430) [16,17], Cephalon (CEP-33779) [18], Bristol-Myers Squibb (BMS-911543) [19] and Amgen (1) [20] (Figure 1), whereas JAK3 selective inhibitors have been identified by Novartis (2) [21], Roche (3) [22] and Vertex (VX-509) ( Figure 2). VX-509 has progressed to Phase II studies in rheumatoid arthritis and has been reported to show < 10-fold selectivity for JAK3 at the kinase level but considerably better selectivity in cellular assays [23].…”