6IAR

Tricyclic indazoles a novel class of selective estrogen receptor degrader antagonists

Summary for 6IAR

• Entry DOI: 10.2210/pdb6iar/pdb
• Descriptor: Estrogen receptor, 3-[4-[(6~{R})-7-(2-methylpropyl)-3,6,8,9-tetrahydropyrazolo[4,3-f]isoquinolin-6-yl]phenyl]propanoic acid (3 entities in total)
• Functional Keywords: nuclear hormone receptor inhibitor downregulation estrogen receptor modulators, dna binding protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 27470.29

Authors

Scott, J.S.,Bailey, A.,Buttar, D.,Carbajo, R.J.,Curwen, J.,Davies, R.D.M.,Degorce, S.L.,Donald, C.,Gangl, E.,Greenwood, R.,Groombridge, S.D.,Johnson, T.,Lamont, S.,Lawson, M.,Lister, A.,Morrow, C.,Moss, T.,Pink, J.H.,Polanski, R. (deposition date: 2018-11-27, release date: 2019-01-23, Last modification date: 2024-05-15)

Primary citation

Scott, J.S.,Bailey, A.,Buttar, D.,Carbajo, R.J.,Curwen, J.,Davey, P.R.J.,Davies, R.D.M.,Degorce, S.L.,Donald, C.,Gangl, E.,Greenwood, R.,Groombridge, S.D.,Johnson, T.,Lamont, S.,Lawson, M.,Lister, A.,Morrow, C.J.,Moss, T.A.,Pink, J.H.,Polanski, R.
Tricyclic Indazoles-A Novel Class of Selective Estrogen Receptor Degrader Antagonists.
J.Med.Chem., 62:1593-1608, 2019

PubMed Abstract: Herein, we report the identification and synthesis of a series of tricyclic indazoles as a novel class of selective estrogen receptor degrader antagonists. Replacement of a phenol, present in our previously reported tetrahydroisoquinoline scaffold, with an indazole group led to the removal of a reactive metabolite signal in an in vitro glutathione trapping assay. Further optimization, guided by X-ray crystal structures and NMR conformational work, varied the alkyl side chain and pendant aryl group and resulted in compounds with low turnover in human hepatocytes and enhanced chemical stability. Compound 9 was profiled as a representative of the series in terms of pharmacology and demonstrated the desired estrogen receptor α degrader-antagonist profile and demonstrated activity in a xenograft model of breast cancer.

PubMed: 30640465
DOI: 10.1021/acs.jmedchem.8b01837

Experimental method

X-RAY DIFFRACTION (1.84 Å)