Structure-based Design of Pyridone-Aminal eFT508 Targeting Dysregulated Translation by Selective Mitogen-activated Protein Kinase Interacting Kinases 1 and 2 (MNK1/2) Inhibition was written by Reich, Siegfried H.;Sprengeler, Paul A.;Chiang, Gary G.;Appleman, James R.;Chen, Joan;Clarine, Jeff;Eam, Boreth;Ernst, Justin T.;Han, Qing;Goel, Vikas K.;Han, Edward Z. R.;Huang, Vera;Hung, Ivy N. J.;Jemison, Adrianna;Jessen, Katti A.;Molter, Jolene;Murphy, Douglas;Neal, Melissa;Parker, Gregory S.;Shaghafi, Michael;Sperry, Samuel;Staunton, Jocelyn;Stumpf, Craig R.;Thompson, Peggy A.;Tran, Chinh;Webber, Stephen E.;Wegerski, Christopher J.;Zheng, Hong;Webster, Kevin R.. And the article was included in Journal of Medicinal Chemistry in 2018.Formula: C6H3BrFNO2 This article mentions the following:
Dysregulated translation of mRNA plays a major role in tumorigenesis. Mitogen-activated protein kinase interacting kinases (MNK)1/2 are key regulators of mRNA translation integrating signals from oncogenic and immune signaling pathways through phosphorylation of eIF4E and other mRNA binding proteins. Modulation of these key effector proteins regulates mRNA, which controls tumor/stromal cell signaling. Compound 23 (eFT508, 6′-((6-aminopyrimidin-4-yl)amino)-8′-methyl-2’H-spiro-[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione hydrochloride), an exquisitely selective, potent dual MNK1/2 inhibitor, was designed to assess the potential for control of oncogene signaling at the level of mRNA translation. The crystal structure-guided design leverages stereoelectronic interactions unique to MNK culminating in a novel pyridone-aminal structure described for the first time in the kinase literature. Compound 23 has potent in vivo antitumor activity in models of diffuse large cell B-cell lymphoma and solid tumors, suggesting that controlling dysregulated translation has real therapeutic potential. Compound 23 is currently being evaluated in Phase 2 clin. trials in solid tumors and lymphoma. Compound 23 is the first highly selective dual MNK inhibitor targeting dysregulated translation being assessed clin. In the experiment, the researchers used many compounds, for example, 5-Bromo-3-fluoropicolinic acid (cas: 669066-91-5Formula: C6H3BrFNO2).
5-Bromo-3-fluoropicolinic acid (cas: 669066-91-5) belongs to pyridine derivatives. Pyridine’s the lone pair does not contribute to the aromatic system but importantly influences the chemical properties of pyridine, as it easily supports bond formation via an electrophilic attack. Several pyridine derivatives play important roles in biological systems. While its biosynthesis is not fully understood, nicotinic acid (vitamin B3) occurs in some bacteria, fungi, and mammals.Formula: C6H3BrFNO2