Structural highlights
6o61 is a 6 chain structure with sequence from [1] and Sus scrofa. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
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| Ligands: | , , , , , , |
| Related: | 6o5m, 6o5n |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
[TBA1B_PIG] Tubulin is the major constituent of microtubules. It binds two moles of GTP, one at an exchangeable site on the beta chain and one at a non-exchangeable site on the alpha chain. [STMN4_HUMAN] Exhibits microtubule-destabilizing activity. [A0A287AGU7_PIG] Tubulin is the major constituent of microtubules. It binds two moles of GTP, one at an exchangeable site on the beta chain and one at a non-exchangeable site on the alpha chain.[RuleBase:RU000352][SAAS:SAAS00031082]
Publication Abstract from PubMed
ABI-231 is a potent, orally bioavailable tubulin inhibitor that interacts with the colchicine binding site and is currently undergoing clinical trials for prostate cancer. Guided by the crystal structure of ABI-231 in complex with tubulin, we performed structure-activity relationship (SAR) studies around the 3-indole moiety that led to the discovery of several potent ABI-231 analogs, most notably 10ab and 10bb. The crystal structures of 10ab and 10bb in complex with tubulin confirmed their improved molecular interactions to the colchicine site. In vitro, biological studies showed that new ABI-231 analogs disrupt tubulin polymerization, promote microtubule fragmentation, and inhibit cancer cell migration. In vivo, analog 10bb not only significantly inhibits primary tumor growth and decreases tumor metastasis in melanoma xenograft models, but also shows a significant ability to overcome paclitaxel resistance in a taxane-resistant PC-3/TxR model. In addition, pharmacological screening suggested that 10bb has a low risk of potential off-target function.
Structure guided design, synthesis, and biological evaluation of 2-(1H-Indol-3-yl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl) Methanone (ABI-231) analogs targeting the colchicine binding site in tubulin.,Wang Q, Arnst K, Wang Y, Kumar GK, Ma D, White SW, Miller DD, Li W, Li W J Med Chem. 2019 Jun 28. doi: 10.1021/acs.jmedchem.9b00706. PMID:31251599[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Wang Q, Arnst K, Wang Y, Kumar GK, Ma D, White SW, Miller DD, Li W, Li W. Structure guided design, synthesis, and biological evaluation of 2-(1H-Indol-3-yl)-1H-imidazol-4-yl)(3,4,5-trimethoxyphenyl) Methanone (ABI-231) analogs targeting the colchicine binding site in tubulin. J Med Chem. 2019 Jun 28. doi: 10.1021/acs.jmedchem.9b00706. PMID:31251599 doi:http://dx.doi.org/10.1021/acs.jmedchem.9b00706
