6SUO

ERa_L536S (L536S/C381S/C471S,C530S) in complex with a tricyclic indole (compound 6)

Summary for 6SUO

• Entry DOI: 10.2210/pdb6suo/pdb
• Descriptor: Estrogen receptor, (~{E})-3-[3,5-bis(fluoranyl)-4-[(1~{R},3~{R})-2-(2-fluoranyl-2-methyl-propyl)-1,3-dimethyl-4,9-dihydro-3~{H}-pyrido[3,4-b]indol-1-yl]phenyl]prop-2-enoic acid (3 entities in total)
• Functional Keywords: oestrogen receptor, oestrogen binding domain, gene regulation
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 58224.04

Authors

Breed, J. (deposition date: 2019-09-16, release date: 2019-10-30, Last modification date: 2024-05-15)

Primary citation

Scott, J.S.,Breed, J.,Carbajo, R.J.,Davey, P.R.,Greenwood, R.,Huynh, H.K.,Klinowska, T.,Morrow, C.J.,Moss, T.A.,Polanski, R.,Nissink, J.W.M.,Varnes, J.,Yang, B.
Building Bridges in a Series of Estrogen Receptor Degraders: An Application of Metathesis in Medicinal Chemistry.
Acs Med.Chem.Lett., 10:1492-1497, 2019

PubMed Abstract: Herein we report the use of metathesis to construct a novel tetracyclic core in a series of estrogen receptor degraders. This improved the chemical stability, as assessed using an NMR-MS based assay, and gave a molecule with excellent physicochemical properties and pharmacokinetics in rat. X-ray crystallography established minimal perturbation of the bridged compounds relative to the unbridged analogues in the receptor binding pocket. Unfortunately, despite retaining excellent binding to ERα, this adversely affected the ability of the compounds to degrade the receptor.

PubMed: 31620239
DOI: 10.1021/acsmedchemlett.9b00370

Experimental method

X-RAY DIFFRACTION (1.74 Å)