Structure-Based Design of Selective Janus Kinase 2 Imidazo[4,5-d]pyrrolo[2,3-b]pyridine Inhibitors

Amy C Hart; Gretchen M Schroeder; Honghe Wan; James Grebinski; Jennifer Inghrim; James Kempson; Junqing Guo; William J Pitts; John S Tokarski; John S Sack; Javed A Khan; Jonathan Lippy; Matthew V Lorenzi; Dan You; Theresa McDevitt; Ragini Vuppugalla; Yueping Zhang; Louis J Lombardo; George L Trainor; Ashok V Purandare

doi:10.1021/acsmedchemlett.5b00225

Structure-Based Design of Selective Janus Kinase 2 Imidazo[4,5-d]pyrrolo[2,3-b]pyridine Inhibitors

ACS Med Chem Lett. 2015 Jul 10;6(8):845-9. doi: 10.1021/acsmedchemlett.5b00225. eCollection 2015 Aug 13.

Authors

Amy C Hart¹, Gretchen M Schroeder¹, Honghe Wan¹, James Grebinski¹, Jennifer Inghrim¹, James Kempson¹, Junqing Guo¹, William J Pitts¹, John S Tokarski¹, John S Sack¹, Javed A Khan¹, Jonathan Lippy¹, Matthew V Lorenzi¹, Dan You¹, Theresa McDevitt¹, Ragini Vuppugalla¹, Yueping Zhang¹, Louis J Lombardo¹, George L Trainor¹, Ashok V Purandare¹

Affiliation

¹ Bristol-Myers Squibb Research & Development , Princeton, New Jersey 08543, United States.

Abstract

Early hit to lead work on a pyrrolopyridine chemotype provided access to compounds with biochemical and cellular potency against Janus kinase 2 (JAK2). Structure-based drug design along the extended hinge region of JAK2 led to the identification of an important H-bond interaction with the side chain of Tyr 931, which improved JAK family selectivity. The 4,5-dimethyl thiazole analogue 18 demonstrated high levels of JAK family selectivity and was identified as a promising lead for the program.

Keywords: Janus kinase 2 (JAK2); Kinase; myeloproliferative neoplasms; structure-based drug design (SBDD); thiazole.