6w4k

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Crystal structure of Lysine Specific Demethylase 1 (LSD1) with CC-90011

Structural highlights

6w4k is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.93Å
Ligands:FAD, V0Y
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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

Histone demethylase LSDl (KDMlA) belongs to the flavin adenine dinucleotide (FAD) dependent family of monoamine oxidases and is vital in regulation of mammalian biology. Dysregulation and overexpression of LSD1 are hallmarks of a number of human diseases, particularly cancers that are characterized as morphologically poorly differentiated. As such, inhibitors of LSD1 have potential to be beneficial as a cancer therapy. The most clinically advanced inhibitors of LSDl are covalent inhibitors derived from tranylcypromine (TCP). Herein, we report the discovery of a novel series of reversible and selective LSDl inhibitors. Exploration of structure-activity relationships (SARs) and optimization of ADME properties resulted in the identification of clinical candidate CC-90011. CC-90011 exhibits potent on-target induction of cellular differentiation in acute myeloid leukemia (AML) and small cell lung cancer (SCLC) cell lines, and antitumor efficacy in patient-derived xenograft (PDX) SCLC models. CC-90011 is currently in phase 2 trials in patients with first line, extensive stage SCLC (ClinicalTrials.gov identifier: NCT03850067).

Discovery of CC-90011: A Potent and Selective Reversible Inhibitor of Lysine Specific Demethylase 1 (LSD1).,Kanouni T, Severin C, Cho RW, Yuen NY, Xu J, Shi L, Lai C, Del Rosario JR, Stansfield RK, Lawton LN, Hosfield D, O'Connell S, Kreilein MM, Tavares-Greco P, Nie Z, Kaldor SW, Veal JM, Stafford JA, Chen YK J Med Chem. 2020 Dec 10;63(23):14522-14529. doi: 10.1021/acs.jmedchem.0c00978. , Epub 2020 Oct 9. PMID:33034194[8]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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Citations
11 reviews cite this structure
An Epigenetic Role of Mitochondria in Cancer.
Liu et al. (2022)
10 more
7 other articles
No citations found

See Also

References

  1. ↑ 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
  2. ↑ 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
  3. ↑ 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
  4. ↑ 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
  5. ↑ 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
  6. ↑ 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
  7. ↑ 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
  8. ↑ Kanouni T, Severin C, Cho RW, Yuen NY, Xu J, Shi L, Lai C, Del Rosario JR, Stansfield RK, Lawton LN, Hosfield D, O'Connell S, Kreilein MM, Tavares-Greco P, Nie Z, Kaldor SW, Veal JM, Stafford JA, Chen YK. Discovery of CC-90011: A Potent and Selective Reversible Inhibitor of Lysine Specific Demethylase 1 (LSD1). J Med Chem. 2020 Dec 10;63(23):14522-14529. PMID:33034194 doi:10.1021/acs.jmedchem.0c00978

Contents


PDB ID 6w4k

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