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Generating selective leads for Mer kinase inhibitors - example of a comprehensive lead-generation strategy

DOI: 10.1021/acs.jmedchem.0c01904 DOI Help

Authors: J. Willem M. Nissink (AstraZeneca) , Sana Bazzaz (X-Chem, Inc) , Carolyn Blackett (AstraZeneca) , Matthew A. Clark (X-Chem, Inc) , Olga Collingwood (AstraZeneca) , Jeremy S. Disch (X-Chem, Inc.) , Diana Gikunju (X-Chem, Inc.) , Kristin Goldberg (AstraZeneca) , John P. Guilinger (X-Chem, Inc) , Elizabeth Hardaker (AstraZeneca) , Edward J. Hennessy (AstraZeneca) , Rachael Jetson (X-Chem, Inc) , Anthony D. Keefe (X-Chem, Inc) , William Mccoull (AstraZeneca) , Lindsay Mcmurray (AstraZeneca) , Allison Olszewski (X-Chem, Inc) , Ross Overman (AstraZeneca) , Alexander Pflug (AstraZeneca) , Marian Preston (AstraZeneca) , Philip B. Rawlins (AstraZeneca) , Emma Rivers (AstraZeneca) , Marianne Schimpl (AstraZeneca) , Paul Smith (AstraZeneca) , Caroline Truman (AstraZeneca) , Elizabeth Underwood (AstraZeneca) , Juli Warwicker (AstraZeneca) , Jon Winter-Holt (AstraZeneca) , Simon Woodcock (AstraZeneca) , Ying Zhang (X-Chem, Inc)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Journal Of Medicinal Chemistry

State: Published (Approved)
Published: March 2021

Abstract: Mer is a member of the TAM (Tyro3, Axl, Mer) kinase family that has been associated with cancer progression, metastasis, and drug resistance. Their essential function in immune homeostasis has prompted an interest in their role as modulators of antitumor immune response in the tumor microenvironment. Here we illustrate the outcomes of an extensive lead-generation campaign for identification of Mer inhibitors, focusing on the results from concurrent, orthogonal high-throughput screening approaches. Data mining, HT (high-throughput), and DECL (DNA-encoded chemical library) screens offered means to evaluate large numbers of compounds. We discuss campaign strategy and screening outcomes, and exemplify series resulting from prioritization of hits that were identified. Concurrent execution of HT and DECL screening successfully yielded a large number of potent, selective, and novel starting points, covering a range of selectivity profiles across the TAM family members and modes of kinase binding, and offered excellent start points for lead development.

Journal Keywords: Peptides and proteins; Drug discovery; Inhibition; Selectivity; Screening assays

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


Instruments: I04-1-Macromolecular Crystallography (fixed wavelength) , I04-Macromolecular Crystallography

Other Facilities: Proxima II at Soleil

Discipline Tags:

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

Technical Tags:

Diffraction Macromolecular Crystallography (MX)