| Structural highlights
4awq is a 2 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | |
| Related: | 1byq, 1osf, 1uy6, 1uy7, 1uy8, 1uy9, 1uyc, 1uyd, 1uye, 1uyf, 1uyg, 1uyh, 1uyi, 1uyk, 1uyl, 1yc1, 1yc3, 1yc4, 1yer, 1yes, 1yet, 2bsm, 2bt0, 2bug, 2byh, 2byi, 2bz5, 2c2l, 2ccs, 2cct, 2ccu, 2fwy, 2fwz, 2jjc, 2uwd, 2vci, 2vcj, 2wi1, 2wi2, 2wi3, 2wi4, 2wi5, 2wi6, 2wi7, 2xab, 2xdk, 2xdl, 2xds, 2xdu, 2xdx, 2xhr, 2xht, 2xhx, 2xjg, 2xjj, 2xjx, 2xk2, 2ye2, 2ye3, 2ye4, 2ye5, 2ye6, 2ye7, 2ye8, 2ye9, 2yea, 2yeb, 2yec, 2yed, 2yee, 2yef, 2yeg, 2yeh, 2yei, 2yej, 2yi0, 2yi5, 2yi6, 2yi7, 2yjw, 2yjx, 2yk2, 2yk9, 2ykb, 2ykc, 2yke, 2yki, 2ykj, 4aif, 4awo, 4awp |
| Activity: | Non-chaperonin molecular chaperone ATPase, with EC number 3.6.4.10 |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
[HS90A_HUMAN] Molecular chaperone that promotes the maturation, structural maintenance and proper regulation of specific target proteins involved for instance in cell cycle control and signal transduction. Undergoes a functional cycle that is linked to its ATPase activity. This cycle probably induces conformational changes in the client proteins, thereby causing their activation. Interacts dynamically with various co-chaperones that modulate its substrate recognition, ATPase cycle and chaperone function.[1] [2]
Publication Abstract from PubMed
With structural guidance, tropane-derived HTS hits were modified to optimize for HSP90 inhibition and a desirable in vivo profile. Through an iterative SAR development process 12i (XL888) was discovered and shown to reduce HSP90 client protein content in PD studies. Furthermore, efficacy experiments performed in a NCI-N87 mouse xenograft model demonstrated tumor regression in some dosing regimens.
Discovery of XL888: A novel tropane-derived small molecule inhibitor of HSP90.,Bussenius J, Blazey CM, Aay N, Anand NK, Arcalas A, Baik T, Bowles OJ, Buhr CA, Costanzo S, Curtis JK, Defina SC, Dubenko L, Heuer TS, Huang P, Jaeger C, Joshi A, Kennedy AR, Kim AI, Lara K, Lee J, Li J, Lougheed JC, Ma S, Malek S, Manalo JC, Martini JF, McGrath G, Nicoll M, Nuss JM, Pack M, Peto CJ, Tsang TH, Wang L, Womble SW, Yakes M, Zhang W, Rice KD Bioorg Med Chem Lett. 2012 Sep 1;22(17):5396-404. Epub 2012 Jul 21. PMID:22877636[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Martinez-Ruiz A, Villanueva L, Gonzalez de Orduna C, Lopez-Ferrer D, Higueras MA, Tarin C, Rodriguez-Crespo I, Vazquez J, Lamas S. S-nitrosylation of Hsp90 promotes the inhibition of its ATPase and endothelial nitric oxide synthase regulatory activities. Proc Natl Acad Sci U S A. 2005 Jun 14;102(24):8525-30. Epub 2005 Jun 3. PMID:15937123 doi:10.1073/pnas.0407294102
- ↑ Forsythe HL, Jarvis JL, Turner JW, Elmore LW, Holt SE. Stable association of hsp90 and p23, but Not hsp70, with active human telomerase. J Biol Chem. 2001 May 11;276(19):15571-4. Epub 2001 Mar 23. PMID:11274138 doi:10.1074/jbc.C100055200
- ↑ Bussenius J, Blazey CM, Aay N, Anand NK, Arcalas A, Baik T, Bowles OJ, Buhr CA, Costanzo S, Curtis JK, Defina SC, Dubenko L, Heuer TS, Huang P, Jaeger C, Joshi A, Kennedy AR, Kim AI, Lara K, Lee J, Li J, Lougheed JC, Ma S, Malek S, Manalo JC, Martini JF, McGrath G, Nicoll M, Nuss JM, Pack M, Peto CJ, Tsang TH, Wang L, Womble SW, Yakes M, Zhang W, Rice KD. Discovery of XL888: A novel tropane-derived small molecule inhibitor of HSP90. Bioorg Med Chem Lett. 2012 Sep 1;22(17):5396-404. Epub 2012 Jul 21. PMID:22877636 doi:10.1016/j.bmcl.2012.07.052
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