| Structural highlights
6hdn is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | , , |
| Gene: | ATAD2, L16, PRO2000 (HUMAN) |
| Activity: | Adenosinetriphosphatase, with EC number 3.6.1.3 |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
[ATAD2_HUMAN] May be a transcriptional coactivator of the nuclear receptor ESR1 required to induce the expression of a subset of estradiol target genes, such as CCND1, MYC and E2F1. May play a role in the recruitment or occupancy of CREBBP at some ESR1 target gene promoters. May be required for histone hyperacetylation. Involved in the estrogen-induced cell proliferation and cell cycle progression of breast cancer cells.[1]
Publication Abstract from PubMed
ATAD2 is a cancer-associated protein whose bromodomain has been described as among the least druggable of its class. In our recent disclosure of the first chemical probe against this bromodomain, GSK8814 (6), we described the use of a conformationally constrained methoxy piperidine to gain selectivity over the BET bromodomains. Here we describe an orthogonal conformational restriction strategy of the piperidine ring to give potent and selective tropane inhibitors and show structural insights into why this was more challenging than expected. Greater understanding of why different rational approaches succeeded or failed should help in the future design of selectivity in the bromodomain family.
Aiming to Miss a Moving Target: Bromo and Extra Terminal Domain (BET) Selectivity in Constrained ATAD2 Inhibitors.,Bamborough P, Chung CW, Furze RC, Grandi P, Michon AM, Watson RJ, Mitchell DJ, Barnett H, Prinjha RK, Rau C, Sheppard RJ, Werner T, Demont EH J Med Chem. 2018 Sep 18. doi: 10.1021/acs.jmedchem.8b00862. PMID:30226378[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Zou JX, Revenko AS, Li LB, Gemo AT, Chen HW. ANCCA, an estrogen-regulated AAA+ ATPase coactivator for ERalpha, is required for coregulator occupancy and chromatin modification. Proc Natl Acad Sci U S A. 2007 Nov 13;104(46):18067-72. Epub 2007 Nov 12. PMID:17998543 doi:http://dx.doi.org/10.1073/pnas.0705814104
- ↑ Bamborough P, Chung CW, Furze RC, Grandi P, Michon AM, Watson RJ, Mitchell DJ, Barnett H, Prinjha RK, Rau C, Sheppard RJ, Werner T, Demont EH. Aiming to Miss a Moving Target: Bromo and Extra Terminal Domain (BET) Selectivity in Constrained ATAD2 Inhibitors. J Med Chem. 2018 Sep 18. doi: 10.1021/acs.jmedchem.8b00862. PMID:30226378 doi:http://dx.doi.org/10.1021/acs.jmedchem.8b00862
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