| Structural highlights
Function
RCOR1_HUMAN Essential component of the BHC complex, a corepressor complex that represses transcription of neuron-specific genes in non-neuronal cells. The BHC complex is recruited at RE1/NRSE sites by REST and acts by deacetylating and demethylating specific sites on histones, thereby acting as a chromatin modifier. In the BHC complex, it serves as a molecular beacon for the recruitment of molecular machinery, including MeCP2 and SUV39H1, that imposes silencing across a chromosomal interval. Plays a central role in demethylation of Lys-4 of histone H3 by promoting demethylase activity of KDM1A on core histones and nucleosomal substrates. It also protects KDM1A from the proteasome. Component of a RCOR/GFI/KDM1A/HDAC complex that suppresses, via histone deacetylase (HDAC) recruitment, a number of genes implicated in multilineage blood cell development and controls hematopoietic differentiation.[1] [2] [3] [4] [5] [6] [7]
Publication Abstract from PubMed
The balance of methylation levels at histone H3 lysine 4 (H3K4) is regulated by KDM1A (LSD1). KDM1A is overexpressed in several tumor types, thus representing an emerging target for the development of novel cancer therapeutics. We have previously described ( Part 1, DOI 10.1021.acs.jmedchem.6b01018 ) the identification of thieno[3,2-b]pyrrole-5-carboxamides as novel reversible inhibitors of KDM1A, whose preliminary exploration resulted in compound 2 with biochemical IC50 = 160 nM. We now report the structure-guided optimization of this chemical series based on multiple ligand/KDM1A-CoRest cocrystal structures, which led to several extremely potent inhibitors. In particular, compounds 46, 49, and 50 showed single-digit nanomolar IC50 values for in vitro inhibition of KDM1A, with high selectivity in secondary assays. In THP-1 cells, these compounds transcriptionally affected the expression of genes regulated by KDM1A such as CD14, CD11b, and CD86. Moreover, 49 and 50 showed a remarkable anticlonogenic cell growth effect on MLL-AF9 human leukemia cells.
Thieno[3,2-b]pyrrole-5-carboxamides as New Reversible Inhibitors of Histone Lysine Demethylase KDM1A/LSD1. Part 2: Structure-Based Drug Design and Structure-Activity Relationship.,Vianello P, Sartori L, Amigoni F, Cappa A, Faga G, Fattori R, Legnaghi E, Ciossani G, Mattevi A, Meroni G, Moretti L, Cecatiello V, Pasqualato S, Romussi A, Thaler F, Trifiro P, Villa M, Botrugno OA, Dessanti P, Minucci S, Vultaggio S, Zagarri E, Varasi M, Mercurio C J Med Chem. 2017 Feb 27. doi: 10.1021/acs.jmedchem.6b01019. PMID:28186757[8]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Ballas N, Battaglioli E, Atouf F, Andres ME, Chenoweth J, Anderson ME, Burger C, Moniwa M, Davie JR, Bowers WJ, Federoff HJ, Rose DW, Rosenfeld MG, Brehm P, Mandel G. Regulation of neuronal traits by a novel transcriptional complex. Neuron. 2001 Aug 16;31(3):353-65. PMID:11516394
- ↑ You A, Tong JK, Grozinger CM, Schreiber SL. CoREST is an integral component of the CoREST- human histone deacetylase complex. Proc Natl Acad Sci U S A. 2001 Feb 13;98(4):1454-8. PMID:11171972 doi:10.1073/pnas.98.4.1454
- ↑ Hakimi MA, Bochar DA, Chenoweth J, Lane WS, Mandel G, Shiekhattar R. A core-BRAF35 complex containing histone deacetylase mediates repression of neuronal-specific genes. Proc Natl Acad Sci U S A. 2002 May 28;99(11):7420-5. PMID:12032298 doi:10.1073/pnas.112008599
- ↑ Lunyak VV, Burgess R, Prefontaine GG, Nelson C, Sze SH, Chenoweth J, Schwartz P, Pevzner PA, Glass C, Mandel G, Rosenfeld MG. Corepressor-dependent silencing of chromosomal regions encoding neuronal genes. Science. 2002 Nov 29;298(5599):1747-52. Epub 2002 Oct 24. PMID:12399542 doi:10.1126/science.1076469
- ↑ Hakimi MA, Dong Y, Lane WS, Speicher DW, Shiekhattar R. A candidate X-linked mental retardation gene is a component of a new family of histone deacetylase-containing complexes. J Biol Chem. 2003 Feb 28;278(9):7234-9. Epub 2002 Dec 18. PMID:12493763 doi:10.1074/jbc.M208992200
- ↑ Shi YJ, Matson C, Lan F, Iwase S, Baba T, Shi Y. Regulation of LSD1 histone demethylase activity by its associated factors. Mol Cell. 2005 Sep 16;19(6):857-64. PMID:16140033 doi:10.1016/j.molcel.2005.08.027
- ↑ Lee MG, Wynder C, Cooch N, Shiekhattar R. An essential role for CoREST in nucleosomal histone 3 lysine 4 demethylation. Nature. 2005 Sep 15;437(7057):432-5. Epub 2005 Aug 3. PMID:16079794 doi:10.1038/nature04021
- ↑ Vianello P, Sartori L, Amigoni F, Cappa A, Faga G, Fattori R, Legnaghi E, Ciossani G, Mattevi A, Meroni G, Moretti L, Cecatiello V, Pasqualato S, Romussi A, Thaler F, Trifiro P, Villa M, Botrugno OA, Dessanti P, Minucci S, Vultaggio S, Zagarri E, Varasi M, Mercurio C. Thieno[3,2-b]pyrrole-5-carboxamides as New Reversible Inhibitors of Histone Lysine Demethylase KDM1A/LSD1. Part 2: Structure-Based Drug Design and Structure-Activity Relationship. J Med Chem. 2017 Feb 27. doi: 10.1021/acs.jmedchem.6b01019. PMID:28186757 doi:http://dx.doi.org/10.1021/acs.jmedchem.6b01019
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