5kr7
From Proteopedia
KDM4C bound to pyrazolo-pyrimidine scaffold
Structural highlights
Function[KDM4C_HUMAN] Histone demethylase that specifically demethylates 'Lys-9' and 'Lys-36' residues of histone H3, thereby playing a central role in histone code. Does not demethylate histone H3 'Lys-4', H3 'Lys-27' nor H4 'Lys-20'. Demethylates trimethylated H3 'Lys-9' and H3 'Lys-36' residue, while it has no activity on mono- and dimethylated residues. Demethylation of Lys residue generates formaldehyde and succinate.[1] Publication Abstract from PubMedThis communication describes the identification and optimization of a series of pan-KDM5 inhibitors derived from compound 1, a hit initially identified against KDM4C. Compound 1 was optimized to afford compound 20, a 10nM inhibitor of KDM5A. Compound 20 is highly selective for the KDM5 enzymes versus other histone lysine demethylases and demonstrates activity in a cellular assay measuring the increase in global histone 3 lysine 4 tri-methylation (H3K4me3). In addition compound 20 has good ADME properties, excellent mouse PK, and is a suitable starting point for further optimization. Identification of potent, selective KDM5 inhibitors.,Gehling VS, Bellon SF, Harmange JC, LeBlanc Y, Poy F, Odate S, Buker S, Lan F, Arora S, Williamson KE, Sandy P, Cummings RT, Bailey CM, Bergeron L, Mao W, Gustafson A, Liu Y, VanderPorten E, Audia JE, Trojer P, Albrecht BK Bioorg Med Chem Lett. 2016 Sep 1;26(17):4350-4. doi: 10.1016/j.bmcl.2016.07.026. , Epub 2016 Jul 19. PMID:27476424[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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