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Fragment-based discovery of JAK-2 inhibitors.

Antonysamy S, Hirst G, Park F, Sprengeler P, Stappenbeck F, Steensma R, Wilson M, Wong M
Bioorg Med Chem Lett 19 279-82 (2009)
Related entries: 3e62, 3e64

Cited: 32 times
EuropePMC logo PMID: 19019674

Abstract

Fragment-based hit identification coupled with crystallographically enabled structure-based drug design was used to design potent inhibitors of JAK-2. After two iterations from fragment 1, we were able to increase potency by greater than 500-fold to provide sulfonamide 13, a 78-nM JAK-2 inhibitor.

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  1. The use of structural biology in Janus kinase targeted drug discovery. Alicea-Velázquez NL, Boggon TJ. Curr Drug Targets 12 546-555 (2011)

Articles - 3e63 mentioned but not cited (5)

  1. Hydrogen bonding penalty upon ligand binding. Zhao H, Huang D. PLoS One 6 e19923 (2011)
  2. Identification of a novel inhibitor of JAK2 tyrosine kinase by structure-based virtual screening. Kiss R, Polgár T, Kirabo A, Sayyah J, Figueroa NC, List AF, Sokol L, Zuckerman KS, Gali M, Bisht KS, Sayeski PP, Keseru GM. Bioorg. Med. Chem. Lett. 19 3598-3601 (2009)
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  4. Rapid Identification of Inhibitors and Prediction of Ligand Selectivity for Multiple Proteins: Application to Protein Kinases. Ma Z, Huang SY, Cheng F, Zou X. J Phys Chem B 125 2288-2298 (2021)
  5. Vortioxetine hydrobromide inhibits the growth of gastric cancer cells in vivo and in vitro by targeting JAK2 and SRC. Li M, Duan L, Wu W, Li W, Zhao L, Li A, Lu X, He X, Dong Z, Liu K, Jiang Y. Oncogenesis 12 24 (2023)


Reviews citing this publication (8)

  1. Structural biology in fragment-based drug design. Murray CW, Blundell TL. Curr. Opin. Struct. Biol. 20 497-507 (2010)
  2. Perspectives for the use of structural information and chemical genetics to develop inhibitors of Janus kinases. Haan C, Behrmann I, Haan S. J. Cell. Mol. Med. 14 504-527 (2010)
  3. Comprehensive survey of chemical libraries for drug discovery and chemical biology: 2009. Dolle RE, Bourdonnec BL, Worm K, Morales GA, Thomas CJ, Zhang W. J Comb Chem 12 765-806 (2010)
  4. Drugging challenging targets using fragment-based approaches. Coyne AG, Scott DE, Abell C. Curr Opin Chem Biol 14 299-307 (2010)
  5. The recent medicinal chemistry development of Jak2 tyrosine kinase small molecule inhibitors. Baskin R, Majumder A, Sayeski PP. Curr. Med. Chem. 17 4551-4558 (2010)
  6. The current status and the future of JAK2 inhibitors for the treatment of myeloproliferative diseases. Hitoshi Y, Lin N, Payan DG, Markovtsov V. Int. J. Hematol. 91 189-200 (2010)
  7. Recent developments on JAK2 inhibitors: a patent review. Kiss R, Sayeski PP, Keserũ GM. Expert Opin Ther Pat 20 471-495 (2010)
  8. Protein crystallography and fragment-based drug design. Caliandro R, Belviso DB, Aresta BM, de Candia M, Altomare CD. Future Med Chem 5 1121-1140 (2013)

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  2. Synthesis and evaluation of indazole based analog sensitive Akt inhibitors. Okuzumi T, Ducker GS, Zhang C, Aizenstein B, Hoffman R, Shokat KM. Mol Biosyst 6 1389-1402 (2010)
  3. Dual inhibitors of Janus kinase 2 and 3 (JAK2/3): designing by pharmacophore- and docking-based virtual screening approach. Jasuja H, Chadha N, Kaur M, Silakari O. Mol. Divers. 18 253-267 (2014)
  4. Structure-function correlation of G6, a novel small molecule inhibitor of Jak2: indispensability of the stilbenoid core. Majumder A, Govindasamy L, Magis A, Kiss R, Polgár T, Baskin R, Allan RW, Agbandje-McKenna M, Reuther GW, Keseru GM, Bisht KS, Sayeski PP. J. Biol. Chem. 285 31399-31407 (2010)
  5. The stilbenoid tyrosine kinase inhibitor, G6, suppresses Jak2-V617F-mediated human pathological cell growth in vitro and in vivo. Kirabo A, Embury J, Kiss R, Polgár T, Gali M, Majumder A, Bisht KS, Cogle CR, Keseru GM, Sayeski PP. J. Biol. Chem. 286 4280-4291 (2011)
  6. 2-Aminopyrazolo[1,5-a]pyrimidines as potent and selective inhibitors of JAK2. Ledeboer MW, Pierce AC, Duffy JP, Gao H, Messersmith D, Salituro FG, Nanthakumar S, Come J, Zuccola HJ, Swenson L, Shlyakter D, Mahajan S, Hoock T, Fan B, Tsai WJ, Kolaczkowski E, Carrier S, Hogan JK, Zessis R, Pazhanisamy S, Bennani YL. Bioorg. Med. Chem. Lett. 19 6529-6533 (2009)
  7. Fragment-Based Discovery of 6-Arylindazole JAK Inhibitors. Ritzén A, Sørensen MD, Dack KN, Greve DR, Jerre A, Carnerup MA, Rytved KA, Bagger-Bahnsen J. ACS Med Chem Lett 7 641-646 (2016)
  8. In silico identification of natural product inhibitors of JAK2. Zhong HJ, Lin S, Tam IL, Lu L, Chan DS, Ma DL, Leung CH. Methods 71 21-25 (2015)
  9. Design and evaluation of 3-aminopyrazolopyridinone kinase inhibitors inspired by the natural product indirubin. Smyth LA, Matthews TP, Collins I. Bioorg. Med. Chem. 19 3569-3578 (2011)
  10. Discovery of a novel pyrazole series of group X secreted phospholipase A2 inhibitor (sPLA2X) via fragment based virtual screening. Chen H, Knerr L, Åkerud T, Hallberg K, Öster L, Rohman M, Österlund K, Beisel HG, Olsson T, Brengdhal J, Sandmark J, Bodin C. Bioorg. Med. Chem. Lett. 24 5251-5255 (2014)
  11. AlphaSpace 2.0: Representing Concave Biomolecular Surfaces Using β-Clusters. Katigbak J, Li H, Rooklin D, Zhang Y. J Chem Inf Model 60 1494-1508 (2020)
  12. Discovery of Tyk2 inhibitors via the virtual site-directed fragment-based drug design. Jang WD, Kim JT, Son HY, Park SY, Cho YS, Koo TS, Lee H, Kang NS. Bioorg. Med. Chem. Lett. 25 3947-3952 (2015)
  13. Pharmacophore and docking-based virtual screening approach for the design of new dual inhibitors of Janus kinase 1 and Janus kinase 2. Jasuja H, Chadha N, Kaur M, Silakari O. SAR QSAR Environ Res 25 617-636 (2014)
  14. A novel inhibitor of the new antibiotic resistance protein OptrA. Zhong X, Xiang H, Wang T, Zhong L, Ming D, Nie L, Cao F, Li B, Cao J, Mu D, Ruan K, Wang L, Wang D. Chem Biol Drug Des 92 1458-1467 (2018)
  15. Artocarpus altilis CG-901 alters critical nodes in the JH1-kinase domain of Janus kinase 2 affecting upstream JAK/STAT3 signaling. Nash O, Omotuyi O, Lee J, Kwon BM, Ogbadu L. J Mol Model 21 280 (2015)
  16. Comparison of Data Fusion Methods as Consensus Scores for Ensemble Docking. Bajusz D, Rácz A, Héberger K. Molecules 24 (2019)
  17. Discovery of a novel kinase hinge binder fragment by dynamic undocking. Rachman M, Bajusz D, Hetényi A, Scarpino A, Merő B, Egyed A, Buday L, Barril X, Keserű GM. RSC Med Chem 11 552-558 (2020)
  18. The discovery of reverse tricyclic pyridone JAK2 inhibitors. Part 2: lead optimization. Siu T, Kumarasinghe SE, Altman MD, Katcher M, Northrup A, White C, Rosenstein C, Mathur A, Xu L, Chan G, Bachman E, Bouthillette M, Dinsmore CJ, Marshall CG, Young JR. Bioorg. Med. Chem. Lett. 24 1466-1471 (2014)


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