Discovery, Characterization, and Structure-Based Optimization of Small-Molecule In Vitro and In Vivo Probes for Human DNA Polymerase Theta

被引：26

作者：

Stockley, Martin L. ^{[1
]}

Ferdinand, Amanda ^{[2
]}

Benedetti, Giovanni

Blencowe, Peter ^{[2
]}

Boyd, Susan M.

Calder, Mat ^{[2
]}

Charles, Mark D. ^{[2
]}

Edwardes, Lucy V. ^{[1
]}

Ekwuru, Tennyson ^{[2
]}

Finch, Harry

Galbiati, Alessandro ^{[1
]}

Geo, Lerin ^{[1
]}

Grande, Diego ^{[1
]}

Grinkevich, Vera ^{[1
]}

Holliday, Nicholas D. ^{[4
]}

Krajewski, Wojciech W. ^{[2
]}

MacDonald, Ellen ^{[2
]}

Majithiya, Jayesh B. ^{[1
]}

McCarron, Hollie ^{[2
]}

McWhirter, Claire L. ^{[1
]}

Patel, Viral ^{[4
]}

Pedder, Chris ^{[2
]}

Rajendra, Eason ^{[1
]}

Ranzani, Macro ^{[1
]}

Rigoreau, Laurent J. M. ^{[2
]}

Robinson, Helen M. R. ^{[1
]}

Schaedler, Theresia ^{[1
]}

Sirina, Julija ^{[4
]}

Smith, Graeme C. M. ^{[1
]}

Swarbrick, Martin E. ^{[2
]}

Turnbull, Andrew P. ^{[2
]}

Willis, Simon ^{[2
]}

Heald, Robert A. ^{[1
,2
,3
,4
]}

机构：

[1] Artios Pharm Ltd, Cambridge CB22 3FH, England

[2] Canc Res Horizons Therapeut Innovat, Cambridge CB22 3AT, England

[3] St Johns Innovat Ctr, Comp Chem Solut Ltd, Cambridge CB4 0WS, England

[4] Excellerate Biosci Ltd, Nottingham NG1 1GF, England

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2022年 / 65卷 / 20期

关键词：

DAMAGE RESPONSE;

D O I：

10.1021/acs.jmedchem.2c01142

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Human DNA polymerase theta (Pol0), which is essential for microhomology-mediated DNA double strand break repair, has been proposed as an attractive target for the treatment of BRCA deficient and other DNA repair pathway defective cancers. As previously reported, we recently identified the first selective small molecule Pol0 in vitro probe, 22 (ART558), which recapitulates the phenotype of Pol0 loss, and in vivo probe, 43 (ART812), which is efficacious in a model of PARP inhibitor resistant TNBC in vivo. Here we describe the discovery, biochemical and biophysical characterization of these probes including small molecule ligand co-crystal structures with Pol0. The crystallographic data provides a basis for understanding the unique mechanism of inhibition of these compounds which is dependent on stabilization of a "closed" enzyme conformation. Additionally, the structural biology platform provided a basis for rational optimization based primarily on reduced ligand conformational flexibility.

引用

页码：13879 / 13891

页数：13

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