Human Transcription Factors Annotated Library

Description

•Transcription Factors are proteins that regulate gene reading from DNA sequences

•A direct modulation of a Transcription Factor activity by small molecules can be achieved through

-Mimetics of peptide motifs that bind at either activation domain (AD) or signal-sensing domain (SSD)
-Mimetics of DNA motifs that bind at a DNA-binding domain (DBD)

•Transcription Factors are promising therapeutic targets for

-Oncology, e.g. immunological response modulators, tumor suppressors, oncogenes regulators
-Metabolic diseases, e.g. diabetes, osteoporosis, high-density lipoproteins (HDL) regulation
-Cardiovascular system, e.g. atherosclerosis, thrombosis
-Inflammation, e.g. autoimmune diseases, immune response suppression

A unique collection of small molecule compounds with annotated activities for Transcription Factors targets

• Annotated activities : 36 transcription factors targets
• Express Delivery : 480 compounds
• Complete Version : 5278 compounds

Library Composition

Data sources of annotations : Pharos, ChEMBL 25, PubChem, PubMed, Current Patent Literature (CAS, Integrity)

IDNUMBER – ChemDiv Catalog ID (in some instances the same IDNUMBER might have multiple annotation entries due to multiple data sources or because having activity against multiple similar targets);

UNIPROT – SwissProt and ChEMBL Target accesion ID; 

Type – character of the measured activity;

Value – Active compounds selection criteria, included only compounds with reported activities < 5 µM;

pubmed_id – PubMed record entry; 

doi, patent_id – journal or patent reference to a publication of original data;  

For screening data extracted from PubChem, see column assay_description for entry names PUBCHEM_BIOASSAY

Example of Annotations - an Excel file structure

IDNUMBER	UNIPROT	Target Name	Type	Relation	Value	Units	pubmed_id	doi	patent_id	Target Description	assay_description
1431-2228	Q9UBN7	Histone deacetylase 6	IC50	=	1590	nM			US-8748451-B2	Histone deacetylase 6	Activity Assay: HDAC assay is performed using fluorescently-labeled acetylated substrate which comprises an acetylated lysine side chain.
0896-4245	O60341	Lysine-specific histone demethylase 1	IC50	=	218	nM			US-8987335-B2	Lysine-specific histone demethylase 1A	Inhibitor Screening Assay: The primary assay for compound inhibitory activity
1741-0974	Q9Y294	Histone chaperone ASF1A	IC50	=	600	nM	25582598	10.1016/j.bmcl.2014.11.067		Histone chaperone ASF1A	Inhibition of His-tagged human Asf1a binding with H3/H4 by ALPHA assay
G266-0266	P55201	Peregrin	IC50	=	100	nM	25408830	10.1021/ml5002932		Peregrin	Binding affinity to 6H-Flag-tagged Tev-BRPF1 (622-738 aa) (unknown origin) by TR-FRET
8015-7476	O96028	Histone-lysine N-methyltransferase NSD2	AC50	=	113	nM				Histone-lysine N-methyltransferase NSD2	PubChem BioAssay. Development of Small Molecule Probes of the Histone Methyltransferase NSD2
5067-3370	O00255	Menin/Histone-lysine N-methyltransferase MLL	Potency	=	0.1	nM				Menin	PUBCHEM_BIOASSAY: qHTS Assay for Inhibitors Targeting the Menin-MLL Interaction in MLL Related Leukemias
8016-5992	Q9BY41	Histone deacetylase	IC50	=	515	nM	11831887	10.1021/jm015568c		Histone deacetylase 8	Concentration required to inhibit human Histone deacetylase (HDAC) enzyme by 50%
0402-0164	Q9BY41	Histone deacetylase	Ki	=	8.21	nM	19520580	10.1016/j.bmc.2009.05.042		Histone deacetylase 8	Inhibition of HDAC in human Hela cells nuclear extracts by fluorimetric assay
1822-0862	Q9Y6K1	DNMT3A2/3L complex	IC50	=	500	nM	25406944	10.1021/jm500843d		DNA (cytosine-5)-methyltransferase 3A	Inhibition of His6-tagged human recombinant DNMT3A/DNMT3L
R092-0055	P04150	Glucocorticoid receptor	Ki	=	5.5	nM	8627601	10.1021/jm950747d		Glucocorticoid receptor	Binding affinity was determined for human glucocorticoid receptor(hGR).

Publications

1.J. Med. Chem. 2016 59(4):1642-1647. Discovery of a Chemical Tool Inhibitor Targeting the Bromodomains of TRIM24 and BRPF. Bennett J Fedorov O Tallant C Monteiro O Meier J Gamble V Savitsky P Nunez-Alonso GA Haendler B Rogers C Brennan PE Müller S Knapp S.

2.J. Med. Chem. 2013 56(4):1772-1776. Potent and selective inhibition of histone deacetylase 6 (HDAC6) does not require a surface-binding motif. Wagner FF Olson DE Gale JP Kaya T Weïwer M Aidoud N Thomas M Davoine EL Lemercier BC Zhang YL Holson EB.

3.J. Med. Chem. 2015 58(6):2569-2583. Targeting DNA methylation with small molecules: what's next? Erdmann A Halby L Fahy J Arimondo PB.

4.J. Med. Chem. 2007 50(26):6519-6534. Nonsteroidal glucocorticoid agonists: tetrahydronaphthalenes with alternative steroidal A-ring mimetics possessing dissociated (transrepression/transactivation) efficacy selectivity. Biggadike K Boudjelal M Clackers M Coe DM Demaine DA Hardy GW Humphreys D Inglis GG Johnston MJ Jones HT House D Loiseau R Needham D Skone PA Uings I Veitch G Weingarten GG McLay IM Macdonald SJ.

5.Proc. Natl. Acad. Sci. U.S.A. 2007 104(49): 19244-19249. Antiinflammatory glucocorticoid receptor ligand with reduced side effects exhibits an altered protein-protein interaction profile. Miner JN Ardecky B Benbatoul K Griffiths K Larson CJ Mais DE Marschke K Rosen J Vajda E Zhi L Negro-Vilar A.

6.ACS Med. Chem. Lett. 2014 5(12):1318-1323. Optimization of drug-like properties of nonsteroidal glucocorticoid mimetics and identification of a clinical candidate. Harcken C Riether D Liu P Razavi H Patel U Lee T Bosanac T Ward Y Ralph M Chen Z Souza D Nelson RM Kukulka A Fadra-Khan TN Zuvela-Jelaska L Patel M Thomson DS Nabozny GH.

7.Bioorg. Med. Chem. Lett. 2013 23(19):5442-5447. Discovery of potent and selective nonsteroidal indazolyl amide glucocorticoid receptor agonists. Sheppeck JE Gilmore JL Xiao HY Dhar TG Nirschl D Doweyko AM Sack JS Corbett MJ Malley MF Gougoutas JZ Mckay L Cunningham MD Habte SF Dodd JH Nadler SG Somerville JE Barrish JC.

8.Bioorg. Med. Chem. Lett. 2014 24(22):5265-5267. Identification of the first inverse agonist of retinoid-related orphan receptor (ROR) with dual selectivity for RORβ and RORγt. Gege C Schlüter T Hoffmann T.

9.Bioorg Med Chem 2017 25(2):471-482. Structure-anticonvulsant activity studies in the group of (E)-N-cinnamoyl aminoalkanols derivatives monosubstituted in phenyl ring with 4-Cl 4-CH3 or 2-CH3. Gunia-Krzyżak A Żelaszczyk D Rapacz A Żesławska E Waszkielewicz AM Pańczyk K Słoczyńska K Pękala E Nitek W Filipek B Marona H.

10.J. Med. Chem. 2011 54(24):8616-8631. Identification of benzoxazin-3-one derivatives as novel potent and selective nonsteroidal mineralocorticoid receptor antagonists. Hasui T Matsunaga N Ora T Ohyabu N Nishigaki N Imura Y Igata Y Matsui H Motoyaji T Tanaka T Habuka N Sogabe S Ono M Siedem CS Tang TP Gauthier C De Meese LA Boyd SA Fukumoto S.