3vf9 › Citations

X-ray crystallographic structure-based design of selective thienopyrazole inhibitors for interleukin-2-inducible tyrosine kinase.

McLean LR, Zhang Y, Zaidi N, Bi X, Wang R, Dharanipragada R, Jurcak JG, Gillespy TA, Zhao Z, Musick KY, Choi YM, Barrague M, Peppard J, Smicker M, Duguid M, Parkar A, Fordham J, Kominos D
Bioorg Med Chem Lett 22 3296-300 (2012)
Related entries: 3v5j, 3v5l, 3v8t, 3v8w, 3vf8

Cited: 17 times
EuropePMC logo PMID: 22464456

Abstract

Beginning with a screening hit, unique thienopyrazole-indole inhibitors of Itk (interleukin-2-inducible tyrosine kinase) were designed, synthesized, and crystallized in the target kinase. Although initial compounds were highly active in Itk, they were not selective. Increasing the steric bulk around a tertiary alcohol at the 5-indole position dramatically improved selectivity toward Lyk and Syk, but not Txk. Substitutions at the 3- and 4-indole positions gave less active compounds that remained poorly selective. A difluoromethyl substitution at the 5-position of the thienopyrazole led to a highly potent and selective compound. Phenyl at this position reduced activity and selectivity while pushing the side-chains of Lys-391 and Asp-500 away from the binding pocket. Novel and selective thienopyrazole inhibitors of Itk were designed as a result of combining structure-based design and medicinal chemistry.

Articles - 3vf9 mentioned but not cited (1)

  1. Flavanomarein inhibits high glucose-stimulated epithelial-mesenchymal transition in HK-2 cells via targeting spleen tyrosine kinase. Zhang NN, Kang JS, Liu SS, Gu SM, Song ZP, Li FX, Wang LF, Yao L, Li T, Li LL, Wang Y, Li XJ, Mao XM. Sci Rep 10 439 (2020)


Reviews citing this publication (4)

  1. Inhibitors of BTK and ITK: state of the new drugs for cancer, autoimmunity and inflammatory diseases. Vargas L, Hamasy A, Nore BF, Smith CI. Scand J Immunol 78 130-139 (2013)
  2. Breaking good: the inexorable rise of BTK inhibitors in the treatment of chronic lymphocytic leukaemia. Hutchinson CV, Dyer MJ. Br J Haematol 166 12-22 (2014)
  3. Advances in the design of ITK inhibitors. Charrier JD, Knegtel RM. Expert Opin Drug Discov 8 369-381 (2013)
  4. Bruton's TK inhibitors: structural insights and evolution of clinical candidates. Xing L, Huang A. Future Med Chem 6 675-695 (2014)

Articles citing this publication (12)

  1. Targeting interleukin-2-inducible T-cell kinase (ITK) and resting lymphocyte kinase (RLK) using a novel covalent inhibitor PRN694. Zhong Y, Dong S, Strattan E, Ren L, Butchar JP, Thornton K, Mishra A, Porcu P, Bradshaw JM, Bisconte A, Owens TD, Verner E, Brameld KA, Funk JO, Hill RJ, Johnson AJ, Dubovsky JA. J Biol Chem 290 5960-5978 (2015)
  2. Discovery of novel irreversible inhibitors of interleukin (IL)-2-inducible tyrosine kinase (Itk) by targeting cysteine 442 in the ATP pocket. Harling JD, Deakin AM, Campos S, Grimley R, Chaudry L, Nye C, Polyakova O, Bessant CM, Barton N, Somers D, Barrett J, Graves RH, Hanns L, Kerr WJ, Solari R. J Biol Chem 288 28195-28206 (2013)
  3. Features of reactive cysteines discovered through computation: from kinase inhibition to enrichment around protein degrons. Fowler NJ, Blanford CF, de Visser SP, Warwicker J. Sci Rep 7 16338 (2017)
  4. Discovery and optimization of indazoles as potent and selective interleukin-2 inducible T cell kinase (ITK) inhibitors. Pastor RM, Burch JD, Magnuson S, Ortwine DF, Chen Y, De La Torre K, Ding X, Eigenbrot C, Johnson A, Liimatta M, Liu Y, Shia S, Wang X, Wu LC, Pei Z. Bioorg Med Chem Lett 24 2448-2452 (2014)
  5. Structure-based design and synthesis of potent benzothiazole inhibitors of interleukin-2 inducible T cell kinase (ITK). MacKinnon CH, Lau K, Burch JD, Chen Y, Dines J, Ding X, Eigenbrot C, Heifetz A, Jaochico A, Johnson A, Kraemer J, Kruger S, Krülle TM, Liimatta M, Ly J, Maghames R, Montalbetti CA, Ortwine DF, Pérez-Fuertes Y, Shia S, Stein DB, Trani G, Vaidya DG, Wang X, Bromidge SM, Wu LC, Pei Z. Bioorg Med Chem Lett 23 6331-6335 (2013)
  6. Ligand-based and e-pharmacophore modeling, 3D-QSAR and hierarchical virtual screening to identify dual inhibitors of spleen tyrosine kinase (Syk) and janus kinase 3 (JAK3). Kaur M, Silakari O. J Biomol Struct Dyn 35 3043-3060 (2017)
  7. Identification of a Unique Cytotoxic Thieno[2,3-c]Pyrazole Derivative with Potent and Selective Anticancer Effects In Vitro. Hess JD, Macias LH, Gutierrez DA, Moran-Santibanez K, Contreras L, Medina S, Villanueva PJ, Kirken RA, Varela-Ramirez A, Penichet ML, Aguilera RJ. Biology (Basel) 11 930 (2022)
  8. Oxindole-based SYK and JAK3 dual inhibitors for rheumatoid arthritis: designing, synthesis and biological evaluation. Kaur M, Singh M, Silakari O. Future Med Chem 9 1193-1211 (2017)
  9. A convenient synthesis and biological activity of novel thieno[2,3-c]pyrazole compounds as antimicrobial and anti-inflammatory agents. El-Dean AM, Zaki RM, Abdulrazzaq AY. Bioorg Khim 41 112-120 (2015)
  10. Identification of inactive conformation-selective interleukin-2-inducible T-cell kinase (ITK) inhibitors based on second-harmonic generation. Hantani Y, Iio K, Hantani R, Umetani K, Sato T, Young T, Connell K, Kintz S, Salafsky J. FEBS Open Bio 8 1412-1423 (2018)
  11. Identification of new dual spleen tyrosine kinase (Syk) and phosphoionositide-3-kinase δ (PI3Kδ) inhibitors using ligand and structure-based integrated ideal pharmacophore models. Kaur M, Silakari O. SAR QSAR Environ Res 27 469-499 (2016)
  12. Conformational Selectivity of ITK Inhibitors: Insights from Molecular Dynamics Simulations. Ogawa N, Ohta M, Ikeguchi M. J Chem Inf Model 63 7860-7872 (2023)


Quick links