SAR and in vivo evaluation of 4-aryl-2-aminoalkylpyrimidines as potent and selective Janus kinase 2 (JAK2) inhibitors

Forsyth, Timothy P.; Kearney, Patrick C.; Kim, Byung Gyu; Johnson, Henry W. B.; Aay, Naing; Arcalas, Arlyn; Brown, David S.; Chan, Vicky; Chen, Jeff; Du, Hongwang; Epshteyn, Sergey; Galan, Adam; Huynh, Tai P.; Ibrahim, Mohamed A.; Kane, Brian; Koltun, Elena S.; Mann, Grace; Meyr, Lisa E.; Lee, Matthew S.; Lewis, Gary L.; Noguchi, Robin T.; Pack, Michael; Ridgway, Brian H.; Shi, Xian; Takeuchi, Craig S.; Zu, Peiwen; Leahy, James W.; Nuss, John M.; Aoyama, Ron; Engst, Stefan; Gendreau, Steven; Kassees, Robert; Li, Jia; Lin, Shwu-Hwa; Martini, Jean-François; Stout, Thomas J.; Tong, Philip; Woolfrey, John; Zhang, Wentao; Yu, Peiwen

doi:10.1016/j.bmcl.2012.10.007

Cited by 29 publications

(17 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…H‐bond was also formed between Gly993 (near the Asp‐Phe‐Gly [DFG] motif) of JAK2 and the linker between chlorophenyl and the pyrimidine. Similar H‐bond with Leu932 and Gly993 of JAK2 were also observed in earlier experimental study . Three H‐bond interactions were also observed between the hydroxylamide group of compound 13 and the residues Ser936, Arg938, and Asp939 at the α d ‐helix of JAK2.…”

Section: Resultssupporting

confidence: 85%

“…The hydroxylamide moiety of compound 13 also formed several H‐bond and water‐mediated H‐bond interactions with residues Tyr934, Ser936, Asp939 and Tyr940 at the αD‐Helix of JAK2. Hydrophobic interaction analysis using Ligplot+ showed that compound 13 formed hydrophobic interactions with residues Gly856, Val863, Met929, Glu930, Tyr931, Leu932, Tyr934, Gly935, Asp939, Tyr940, Lys943, and Leu983 …”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Computational Study of Pyrimidin‐2‐Aminopyrazol‐Hydroxamate‐based JAK2 Inhibitors for the Treatment of Myeloproliferative Neoplasms

Keretsu

Bhujbal

Cho

2020

Bulletin Korean Chem Soc

View full text Add to dashboard Cite

Janus Kinase 2 (JAK2) plays a vital role in the cytokine-mediated signaling pathway. Several experimental studies have shown that myeloproliferative neoplasms (MPNs) are associated with the overexpression of JAK2. Hence, JAK2 inhibition is considered to be vital for MPNs therapy. We have performed computational studies on 29 pyrimidin-2-aminopyrazol-hydroxamate-based JAK2 inhibitors. A comparative molecular field analysis (CoMFA) model (q 2 = 0.6 and r 2 = 0.94) was developed. Contour maps from the CoMFA model suggested that electronegative groups at the carbonyl and electropositive groups at the hydroxyl were favored for JAK2 activity. Molecular docking and dynamics simulation revealed that the compound with highest activity (compound 13) formed electrostatic interactions with Leu932, Tyr934, Ser936, Asp939, and Tyr940 of JAK2. Binding free energy calculations showed that hydrophobic and H-bond interactions were the key contributors to the total binding. Results of this study could provide useful insights into designing new JAK2 inhibitors.

show abstract

Section: Resultssupporting

confidence: 85%

Section: Resultsmentioning

confidence: 99%

Computational Study of Pyrimidin‐2‐Aminopyrazol‐Hydroxamate‐based JAK2 Inhibitors for the Treatment of Myeloproliferative Neoplasms

Keretsu

Bhujbal

Cho

2020

Bulletin Korean Chem Soc

View full text Add to dashboard Cite

show abstract

“…Exelixis (San Francisco, CA, USA) described the discovery of their clinical candidate, XL-019 (41) [98]. Following HTS, aminopyrimidine 40 was discovered as a lead with good JAK2 potency and selectivity over JAK3, JAK1 and TYK2.…”

Section: Key Termmentioning

confidence: 99%

Selective JAK Inhibitors

et al. 2014

View full text Add to dashboard Cite

Consisting of four members, JAK1, JAK2, JAK3 and TYK2, the JAK kinases have emerged as important targets for proliferative and immune-inflammatory disorders. Recent progress in the discovery of selective inhibitors has been significant, with selective compounds now reported for each isoform. This article summarizes the current state-of-the-art with a discussion of the most recently described selective compounds. X-ray co-crystal structures reveal the molecular reasons for the observed biochemical selectivity. A concluding analysis of JAK inhibitors in the clinic highlights increased clinical trial activity and diversity of indications. Selective JAK inhibitors, as single agents or in combination regimens, have a very promising future in the treatment of oncology, immune and inflammatory diseases.

show abstract

“…Herein, we utilized the HotLig for the in silico analysis of molecular interaction between ZAA and human JAK2 protein. A structural model of human JAK2 kinase (PDB code: 4BBE) [25], complexed with a selective inhibitor, 3O4 [26], was used for the molecular docking study (Fig. 4A).…”

Section: Zaa Interacted With the Hydrophobic Pocket Of Jak2 To Block mentioning

confidence: 99%

Zhankuic acid A as a novel JAK2 inhibitor for the treatment of concanavalin A-induced hepatitis

Chen

Wang

Chang

et al. 2014

Biochemical Pharmacology

View full text Add to dashboard Cite

SAR and in vivo evaluation of 4-aryl-2-aminoalkylpyrimidines as potent and selective Janus kinase 2 (JAK2) inhibitors

Cited by 29 publications

References 16 publications

Computational Study of Pyrimidin‐2‐Aminopyrazol‐Hydroxamate‐based JAK2 Inhibitors for the Treatment of Myeloproliferative Neoplasms

Computational Study of Pyrimidin‐2‐Aminopyrazol‐Hydroxamate‐based JAK2 Inhibitors for the Treatment of Myeloproliferative Neoplasms

Selective JAK Inhibitors

Zhankuic acid A as a novel JAK2 inhibitor for the treatment of concanavalin A-induced hepatitis

Contact Info

Product

Resources

About