| Structural highlights
Function
[KDM5A_HUMAN] Histone demethylase that specifically demethylates 'Lys-4' of histone H3, thereby playing a central role in histone code. Does not demethylate histone H3 'Lys-9', H3 'Lys-27', H3 'Lys-36', H3 'Lys-79' or H4 'Lys-20'. Demethylates trimethylated and dimethylated but not monomethylated H3 'Lys-4'. May stimulate transcription mediated by nuclear receptors. May be involved in transcriptional regulation of Hox proteins during cell differentiation. May participate in transcriptional repression of cytokines such as CXCL12. Plays a role in the regulation of the circadian rhythm and in maintaining the normal periodicity of the circadian clock. In a histone demethylase-independent manner, acts as a coactivator of the CLOCK-ARNTL/BMAL1-mediated transcriptional activation of PER1/2 and other clock-controlled genes and increases histone acetylation at PER1/2 promoters by inhibiting the activity of HDAC1 (By similarity).[UniProtKB:Q3UXZ9][1] [2] [3] [4] [5]
Publication Abstract from PubMed
A high-throughput screening (HTS) of the Genentech/Roche library identified a novel, uncharged scaffold as a KDM5A inhibitor. Lacking insight into the binding mode, initial attempts to improve inhibitor potency failed to improve potency, and synthesis of analogs was further hampered by the presence of a C-C bond between the pyrrolidine and pyridine. Replacing this with a C-N bond significantly simplified synthesis, yielding pyrazole analog 35, of which we obtained a co-crystal structure with KDM5A. Using structure-based design approach, we identified 50 with improved biochemical, cell potency and reduced MW and lower lipophilicity (LogD) compared with the original hit. Furthermore, 50 showed lower clearance than 9 in mice. In combination with its remarkably low plasma protein binding (PPB) in mice (40%), oral dosing of 50 at 5mg/kg resulted in unbound Cmax approximately 2-fold of its cell potency (PC9 H3K4Me3 0.96muM), meeting our criteria for an in vivo tool compound from a new scaffold.
From a novel HTS hit to potent, selective, and orally bioavailable KDM5 inhibitors.,Liang J, Labadie S, Zhang B, Ortwine DF, Patel S, Vinogradova M, Kiefer JR, Mauer T, Gehling VS, Harmange JC, Cummings R, Lai T, Liao J, Zheng X, Liu Y, Gustafson A, Van der Porten E, Mao W, Liederer BM, Deshmukh G, An L, Ran Y, Classon M, Trojer P, Dragovich PS, Murray L Bioorg Med Chem Lett. 2017 Jul 1;27(13):2974-2981. doi:, 10.1016/j.bmcl.2017.05.016. Epub 2017 May 5. PMID:28512031[6]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Chan SW, Hong W. Retinoblastoma-binding protein 2 (Rbp2) potentiates nuclear hormone receptor-mediated transcription. J Biol Chem. 2001 Jul 27;276(30):28402-12. Epub 2001 May 17. PMID:11358960 doi:http://dx.doi.org/10.1074/jbc.M100313200
- ↑ Benevolenskaya EV, Murray HL, Branton P, Young RA, Kaelin WG Jr. Binding of pRB to the PHD protein RBP2 promotes cellular differentiation. Mol Cell. 2005 Jun 10;18(6):623-35. PMID:15949438 doi:http://dx.doi.org/10.1016/j.molcel.2005.05.012
- ↑ Iwase S, Lan F, Bayliss P, de la Torre-Ubieta L, Huarte M, Qi HH, Whetstine JR, Bonni A, Roberts TM, Shi Y. The X-linked mental retardation gene SMCX/JARID1C defines a family of histone H3 lysine 4 demethylases. Cell. 2007 Mar 23;128(6):1077-88. Epub 2007 Feb 22. PMID:17320160 doi:10.1016/j.cell.2007.02.017
- ↑ Christensen J, Agger K, Cloos PA, Pasini D, Rose S, Sennels L, Rappsilber J, Hansen KH, Salcini AE, Helin K. RBP2 belongs to a family of demethylases, specific for tri-and dimethylated lysine 4 on histone 3. Cell. 2007 Mar 23;128(6):1063-76. Epub 2007 Feb 22. PMID:17320161 doi:S0092-8674(07)00182-1
- ↑ Klose RJ, Yan Q, Tothova Z, Yamane K, Erdjument-Bromage H, Tempst P, Gilliland DG, Zhang Y, Kaelin WG Jr. The retinoblastoma binding protein RBP2 is an H3K4 demethylase. Cell. 2007 Mar 9;128(5):889-900. Epub 2007 Feb 22. PMID:17320163 doi:http://dx.doi.org/10.1016/j.cell.2007.02.013
- ↑ Liang J, Labadie S, Zhang B, Ortwine DF, Patel S, Vinogradova M, Kiefer JR, Mauer T, Gehling VS, Harmange JC, Cummings R, Lai T, Liao J, Zheng X, Liu Y, Gustafson A, Van der Porten E, Mao W, Liederer BM, Deshmukh G, An L, Ran Y, Classon M, Trojer P, Dragovich PS, Murray L. From a novel HTS hit to potent, selective, and orally bioavailable KDM5 inhibitors. Bioorg Med Chem Lett. 2017 Jul 1;27(13):2974-2981. doi:, 10.1016/j.bmcl.2017.05.016. Epub 2017 May 5. PMID:28512031 doi:http://dx.doi.org/10.1016/j.bmcl.2017.05.016
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