Discovery, characterization, and structure-based optimization of small-molecule in vitro and in vivo probes for human DNA polymerase theta

DOI: 10.1021/acs.jmedchem.2c01142

Authors: Martin L. Stockley (Artios Pharma Ltd) , Amanda Ferdinand (Cancer Research Horizons Therapeutic Innovation) , Giovanni Benedetti (Artios Pharma Ltd) , Peter Blencowe (Cancer Research Horizons Therapeutic Innovation) , Susan M. Boyd (CompChem Solutions Ltd) , Mat Calder (Cancer Research Horizons Therapeutic Innovation) , Mark D. Charles (Cancer Research Horizons Therapeutic Innovation) , Lucy V. Edwardes (Artios Pharma Ltd) , Tennyson Ekwuru (Cancer Research Horizons Therapeutic Innovation) , Harry Finch (Artios Pharma Ltd) , Alessandro Galbiati (Artios Pharma Ltd) , Lerin Geo (Artios Pharma Ltd) , Diego Grande (Artios Pharma Ltd) , Vera Grinkevich (Artios Pharma Ltd) , Nicholas D. Holliday (Excellerate Bioscience Ltd) , Wojciech W. Krajewski (Cancer Research Horizons Therapeutic Innovation) , Ellen Macdonald (Cancer Research Horizons Therapeutic Innovation) , Jayesh B. Majithiya (Artios Pharma Ltd) , Hollie Mccarron (Cancer Research Horizons Therapeutic Innovation) , Claire L. Mcwhirter (Artios Pharma Ltd) , Viral Patel (Excellerate Bioscience Ltd) , Chris Pedder (Cancer Research Horizons Therapeutic Innovatio) , Eeson Rajendra (Artios Pharma Ltd) , Marco Ranzani (Artios Pharma Ltd) , Laurent J. M. Rigoreau (Cancer Research Horizons Therapeutic Innovation) , Helen M. R. Robinson (Artios Pharma Ltd) , Theresia Schaedler (Artios Pharma Ltd) , Julija Sirina (Excellerate Bioscience Ltd) , Graeme C. M. Smith (Artios Pharma Ltd) , Martin E. Swarbrick (Cancer Research Horizons Therapeutic Innovation) , Andrew P. Turnbull (Cancer Research Horizons Therapeutic Innovation) , Simon Willis (Cancer Research Horizons Therapeutic Innovation) , Robert A. Heald (Artios Pharma Ltd)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry , VOL 592

State: Published (Approved)
Published: October 2022
Diamond Proposal Number(s): 1541 , 20017

Abstract: Human DNA polymerase theta (Polθ), 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 Polθ in vitro probe, 22 (ART558), which recapitulates the phenotype of Polθ 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 Polθ. 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.

Subject Areas: Biology and Bio-materials, Chemistry, Physics


Instruments: I03-Macromolecular Crystallography

Added On: 10/10/2022 08:30

Discipline Tags:

Non-Communicable Diseases Health & Wellbeing Cancer Biochemistry Chemistry Structural biology Drug Discovery Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)