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

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...

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Bibliographic Details
Published in:ACS medicinal chemistry letters 2015-08, Vol.6 (8), p.845-849
Main Authors: Hart, Amy C, Schroeder, Gretchen M, Wan, Honghe, Grebinski, James, Inghrim, Jennifer, Kempson, James, Guo, Junqing, Pitts, William J, Tokarski, John S, Sack, John S, Khan, Javed A, Lippy, Jonathan, Lorenzi, Matthew V, You, Dan, McDevitt, Theresa, Vuppugalla, Ragini, Zhang, Yueping, Lombardo, Louis J, Trainor, George L, Purandare, Ashok V
Format: Article
Language:English
Subjects:
BASIC BIOLOGICAL SCIENCES
Janus kinase 2 (JAK2)
Kinase
Letter
myeloproliferative neoplasms
structure-based drug design (SBDD)
thiazole
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Summary: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.
ISSN:1948-5875
1948-5875
DOI:10.1021/acsmedchemlett.5b00225