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

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.

Overexpression of Cardiac-Specific Kinase TNNI3K Promotes Mouse Embryonic Stem Cells Differentiation into Cardiomyocytes

“…In the present report, GSK114 is similar to 7-deazapurine in structure, which may be also a new inhibitor of TNNI3K [34]. Importantly, the specificity of GSK114 for TNNI3K translated into the cellular context, as GSK114 exhibited IC 50 = 3300 nM in a cell assay employing B-Raf compared to IC 50 = 100 nM in the TNNI3K cell assay [34, 35]. Recent studies have demonstrated that mi R-223 with antioxidant protein 1 (AOP-1), which is a mitochondrial antioxidant protein [36], can suppress cardiomyocyte hypertrophy via down-regulation of cTnI phosphorylation, which reduces intracellular Ca 2+ and the contractility of cardiomyocytes by directly targeting TNNI3K [37].…”

“…Interestingly a series of small-molecule TNNI3K inhibitors were used to reduce mitochondrial-derived superoxide generation, p38 activation, and infarct size when delivered at reperfusion to mimic clinical intervention [15, 34]. Currently, 7-deazapurine, which is potent and selective type I inhibitors of TNNI3K, are used to elucidate the role of TNNI3K in cardiac biology and used for the development of novel heart failure medicines [35]. In the present report, GSK114 is similar to 7-deazapurine in structure, which may be also a new inhibitor of TNNI3K [34].…”

Design and analysis of the 4-anilino-quin(az)oline kinase inhibition profiles of GAK/SLK/STK10 using quantitative structure activity relationships

“…This can be used to increase potency on target and enhance selectivity over other kinases/targets. Cardiac troponin Iinteracting kinase (TNNI3K) [50][51] and Spleen tyrosine kinase (Syk) 52 have both utilised this to increase potency (by 60-160-fold) and selectivity by the addition of a nitrogen (Figure S1).…”

Hetaryl Bromides Bearing the SO2F Group – Versatile Substrates for Palladium‐Catalyzed C–C Coupling Reactions

“…[45] All other reagents were available from Enamine Ltd. 1 H, 13 [44] [49] When organic solutions were concentrated under reduced pressure, a 35-40°C bath was used.…”