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Discovery and structure-activity relationship of 3-aminopyrid-2-ones as potent and selective interleukin-2 inducible T-cell kinase (Itk) inhibitors.

Charrier JD, Miller A, Kay DP, Brenchley G, Twin HC, Collier PN, Ramaya S, Keily SB, Durrant SJ, Knegtel RM, Tanner AJ, Brown K, Curnock AP, Jimenez JM
J Med Chem 54 2341-50 (2011)
Cited: 26 times
EuropePMC logo PMID: 21391610

Abstract

Interleukin-2 inducible T-cell kinase (Itk) plays a role in T-cell functions, and its inhibition potentially represents an attractive intervention point to treat autoimmune and allergic diseases. Herein we describe the discovery of a series of potent and selective novel inhibitors of Itk. These inhibitors were identified by structure-based design, starting from a fragment generated de novo, the 3-aminopyrid-2-one motif. Functionalization of the 3-amino group enabled rapid enhancement of the inhibitory activity against Itk, while introduction of a substituted heteroaromatic ring in position 5 of the pyridone fragment was key to achieving optimal selectivity over related kinases. A careful analysis of the hydration patterns in the kinase active site was necessary to fully explain the observed selectivity profile. The best molecule prepared in this optimization campaign, 7v, inhibits Itk with a K(i) of 7 nM and has a good selectivity profile across kinases.

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  1. Structure of LRRK2 in Parkinson's disease and model for microtubule interaction. Deniston CK, Salogiannis J, Mathea S, Snead DM, Lahiri I, Matyszewski M, Donosa O, Watanabe R, Böhning J, Shiau AK, Knapp S, Villa E, Reck-Peterson SL, Leschziner AE. Nature 588 344-349 (2020)
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  6. Divide-and-conquer strategy for large-scale Eulerian solvent excluded surface. Zhao R, Wang M, Tong Y, Wei GW. Commun Inf Syst 18 299-329 (2018)


Reviews citing this publication (6)

  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. Approaches to efficiently estimate solvation and explicit water energetics in ligand binding: the use of WaterMap. Yang Y, Lightstone FC, Wong SE. Expert Opin Drug Discov 8 277-287 (2013)
  3. Advances in the design of ITK inhibitors. Charrier JD, Knegtel RM. Expert Opin Drug Discov 8 369-381 (2013)
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  5. From infection niche to therapeutic target: the intracellular lifestyle of Mycobacterium tuberculosis. Rankine-Wilson LI, Shapira T, Sao Emani C, Av-Gay Y. Microbiology (Reading) 167 (2021)
  6. Inducible tyrosine kinase inhibitors: a review of the patent literature (2010 - 2013). Norman P. Expert Opin Ther Pat 24 979-991 (2014)

Articles citing this publication (14)

  1. Rapid decomposition and visualisation of protein-ligand binding free energies by residue and by water. Woods CJ, Malaisree M, Michel J, Long B, McIntosh-Smith S, Mulholland AJ. Faraday Discuss 169 477-499 (2014)
  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. 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 3296-3300 (2012)
  4. Identification of a Novel and Selective Series of Itk Inhibitors via a Template-Hopping Strategy. Alder CM, Ambler M, Campbell AJ, Champigny AC, Deakin AM, Harling JD, Harris CA, Longstaff T, Lynn S, Maxwell AC, Mooney CJ, Scullion C, Singh OM, Smith IE, Somers DO, Tame CJ, Wayne G, Wilson C, Woolven JM. ACS Med Chem Lett 4 948-952 (2013)
  5. Substrate recognition of PLCγ1 via a specific docking surface on Itk. Xie Q, Joseph RE, Fulton DB, Andreotti AH. J Mol Biol 425 683-696 (2013)
  6. Targeting Interleukin-2-Inducible T-cell Kinase (ITK) in T-Cell Related Diseases. Zhong Y, Johnson AJ, Byrd JC, Dubovsky JA. Postdoc J 2 1-11 (2014)
  7. Oxyfunctionalization of pyridine derivatives using whole cells of Burkholderia sp. MAK1. Stankevičiūtė J, Vaitekūnas J, Petkevičius V, Gasparavičiūtė R, Tauraitė D, Meškys R. Sci Rep 6 39129 (2016)
  8. A Role for Hydration in Interleukin-2 Inducible T Cell Kinase (Itk) Selectivity. Knegtel RM, Robinson DD. Mol Inform 30 950-959 (2011)
  9. Auto In Silico Ligand Directing Evolution to Facilitate the Rapid and Efficient Discovery of Drug Lead. Wu F, Zhuo L, Wang F, Huang W, Hao G, Yang G. iScience 23 101179 (2020)
  10. 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)
  11. 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)
  12. Cytotoxic lymphocytes-related gene ITK from a systematic CRISPR screen could predict prognosis of ovarian cancer patients with distant metastasis. Xu M, Huang S, Chen J, Xu W, Xiang R, Piao Y, Zhao S. J Transl Med 19 447 (2021)
  13. Synthesis and profiling of a 3-aminopyridin-2-one-based kinase targeted fragment library: Identification of 3-amino-5-(pyridin-4-yl)pyridin-2(1H)-one scaffold for monopolar spindle 1 (MPS1) and Aurora kinases inhibition. Fearon D, Westwood IM, van Montfort RLM, Bayliss R, Jones K, Bavetsias V. Bioorg Med Chem 26 3021-3029 (2018)
  14. Conformational Selectivity of ITK Inhibitors: Insights from Molecular Dynamics Simulations. Ogawa N, Ohta M, Ikeguchi M. J Chem Inf Model 63 7860-7872 (2023)


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