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Identification of Purines and 7-Deazapurines as Potent and Selective Type I Inhibitors of Troponin I-Interacting Kinase (TNNI3K).

Lawhorn BG, Philp J, Zhao Y, Louer C, Hammond M, Cheung M, Fries H, Graves AP, Shewchuk L, Wang L, Cottom JE, Qi H, Zhao H, Totoritis R, Zhang G, Schwartz B, Li H, Sweitzer S, Holt DA, Gatto GJ, Kallander LS
J Med Chem 58 7431-48 (2015)
Cited: 10 times
EuropePMC logo PMID: 26355916

Abstract

A series of cardiac troponin I-interacting kinase (TNNI3K) inhibitors arising from 3-((9H-purin-6-yl)amino)-N-methyl-benzenesulfonamide (1) is disclosed along with fundamental structure-function relationships that delineate the role of each element of 1 for TNNI3K recognition. An X-ray structure of 1 bound to TNNI3K confirmed its Type I binding mode and is used to rationalize the structure-activity relationship and employed to design potent, selective, and orally bioavailable TNNI3K inhibitors. Identification of the 7-deazapurine heterocycle as a superior template (vs purine) and its elaboration by introduction of C4-benzenesulfonamide and C7- and C8-7-deazapurine substituents produced compounds with substantial improvements in potency (>1000-fold), general kinase selectivity (10-fold improvement), and pharmacokinetic properties (>10-fold increase in poDNAUC). Optimal members of the series have properties suitable for use in in vitro and in vivo experiments aimed at elucidating the role of TNNI3K in cardiac biology and serve as leads for developing novel heart failure medicines.

Articles - 4yff mentioned but not cited (2)

  1. New Insights into 4-Anilinoquinazolines as Inhibitors of Cardiac Troponin I-Interacting Kinase (TNNi3K). Asquith CRM, Laitinen T, Wells CI, Tizzard GJ, Zuercher WJ. Molecules 25 E1697 (2020)
  2. BoBER: web interface to the base of bioisosterically exchangeable replacements. Lešnik S, Škrlj B, Eržen N, Bren U, Gobec S, Konc J, Janežič D. J Cheminform 9 62 (2017)


Reviews citing this publication (2)

  1. Molecular and genetic insights into progressive cardiac conduction disease. Asatryan B, Medeiros-Domingo A. Europace 21 1145-1158 (2019)
  2. The Diverse Roles of TNNI3K in Cardiac Disease and Potential for Treatment. Pham C, Muñoz-Martín N, Lodder EM. Int J Mol Sci 22 6422 (2021)

Articles citing this publication (6)

  1. A Novel Missense Mutation in TNNI3K Causes Recessively Inherited Cardiac Conduction Disease in a Consanguineous Pakistani Family. Ramzan S, Tennstedt S, Tariq M, Khan S, Noor Ul Ayan H, Ali A, Munz M, Thiele H, Korejo AA, Mughal AR, Jamal SZ, Nürnberg P, Baig SM, Erdmann J, Ahmad I. Genes (Basel) 12 1282 (2021)
  2. GSK114: A selective inhibitor for elucidating the biological role of TNNI3K. Lawhorn BG, Philp J, Graves AP, Shewchuk L, Holt DA, Gatto GJ, Kallander LS. Bioorg Med Chem Lett 26 3355-3358 (2016)
  3. A Fluorescence-Based Assay to Probe Inhibitory Effect of Fructose Mimics on GLUT5 Transport in Breast Cancer Cells. Rana N, Aziz MA, Serya RAT, Lasheen DS, Samir N, Wuest F, Abouzid KAM, West FG. ACS Bio Med Chem Au 3 51-61 (2023)
  4. A critical evaluation of protein kinase regulation by activation loop autophosphorylation. Reinhardt R, Leonard TA. Elife 12 e88210 (2023)
  5. Continuation of structure-activity relationship study of novel benzamide derivatives as potential antipsychotics. Xu M, Guo S, Yang F, Wang Y, Wu C, Jiang X, Zhao Q, Chen W, Tian G, Zhu F, Xie Y, Hu T, Wang Z, He Y, Shen J. Arch Pharm (Weinheim) 352 e1800306 (2019)
  6. Discovery of New Pyrrolo[2,3-d]pyrimidine Derivatives as Potential Multi-Targeted Kinase Inhibitors and Apoptosis Inducers. Alotaibi AA, Alanazi MM, Rahman AFMM. Pharmaceuticals (Basel) 16 1324 (2023)


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