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Antibody fragments structurally enable a drug-discovery campaign on the cancer target Mcl-1

DOI: 10.1107/S2059798319014116 DOI Help

Authors: Jakub Luptak (AstraZeneca) , Michal Bista (AstraZeneca) , David Fisher (AstraZeneca) , Liz Flavell (AstraZeneca) , Ning Gao (AstraZeneca) , Kate Wickson (AstraZeneca) , Steven L. Kazmirski (AstraZeneca) , Tina Howard (AstraZeneca) , Philip B. Rawlins (AstraZeneca) , David Hargreaves (AstraZeneca)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: Acta Crystallographica Section D Structural Biology , VOL 75 , PAGES 1003 - 1014

State: Published (Approved)
Published: November 2019

Open Access Open Access

Abstract: Apoptosis is a crucial process by which multicellular organisms control tissue growth, removal and inflammation. Disruption of the normal apoptotic function is often observed in cancer, where cell death is avoided by the overexpression of anti-apoptotic proteins of the Bcl-2 (B-cell lymphoma 2) family, including Mcl-1 (myeloid cell leukaemia 1). This makes Mcl-1 a potential target for drug therapy, through which normal apoptosis may be restored by inhibiting the protective function of Mcl-1. Here, the discovery and biophysical properties of an anti-Mcl-1 antibody fragment are described and the utility of both the scFv and Fab are demonstrated in generating an Mcl-1 crystal system amenable to iterative structure-guided drug design.

Journal Keywords: Mcl-1; scFv; Fab; drug design

Subject Areas: Biology and Bio-materials, Medicine

Instruments: I02-Macromolecular Crystallography , I03-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength) , I04-Macromolecular Crystallography