Structural highlights
Disease
[TNI3K_HUMAN] The disease is caused by mutations affecting the gene represented in this entry.
Function
[TNI3K_HUMAN] May play a role in cardiac physiology.[1]
Publication Abstract from PubMed
Structure-guided progression of a purine-derived series of TNNI3K inhibitors directed design efforts that produced a novel series of 4,6-diaminopyrimidine inhibitors, an emerging kinase binding motif. Herein, we report a detailed understanding of the intrinsic conformational preferences of the scaffold, which impart high specificity for TNNI3K. Further manipulation of the template based on the conformational analysis and additional structure-activity relationship studies provided enhancements in kinase selectivity and pharmacokinetics that furnished an advanced series of potent inhibitors. The optimized compounds (e.g., GSK854) are suitable leads for identifying new cardiac medicines and have been employed as in vivo tools in investigational studies aimed at defining the role of TNNI3K within heart failure.
4,6-Diaminopyrimidines as Highly Preferred Troponin I-Interacting Kinase (TNNI3K) Inhibitors.,Philp J, Lawhorn BG, Graves AP, Shewchuk L, Rivera KL, Jolivette LJ, Holt DA, Gatto GJ Jr., Kallander LS J Med Chem. 2018 Mar 21. doi: 10.1021/acs.jmedchem.8b00125. PMID:29561151[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Zhao Y, Meng XM, Wei YJ, Zhao XW, Liu DQ, Cao HQ, Liew CC, Ding JF. Cloning and characterization of a novel cardiac-specific kinase that interacts specifically with cardiac troponin I. J Mol Med. 2003 May;81(5):297-304. Epub 2003 Apr 30. PMID:12721663 doi:http://dx.doi.org/10.1007/s00109-003-0427-x
- ↑ Philp J, Lawhorn BG, Graves AP, Shewchuk L, Rivera KL, Jolivette LJ, Holt DA, Gatto GJ Jr., Kallander LS. 4,6-Diaminopyrimidines as Highly Preferred Troponin I-Interacting Kinase (TNNI3K) Inhibitors. J Med Chem. 2018 Mar 21. doi: 10.1021/acs.jmedchem.8b00125. PMID:29561151 doi:http://dx.doi.org/10.1021/acs.jmedchem.8b00125
