Small-Molecule Inhibitors That Target Protein–Protein Interactions in the RAD51 Family of Recombinases
Duncan Scott,Anthony G. Coyne,Ashok R. Venkitaraman,Tom L. Blundell,Chris Abell,Marko Hyvönen +5 more
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TLDR
This study reports the development of indole‐based fragments that bind in a shallow surface pocket of a humanised surrogate of RAD51, an ATP‐dependent recombinase that plays a key role in the repair of double‐strand DNA breaks.Abstract:
The development of small molecules that inhibit protein–protein interactions continues to be a challenge in chemical biology and drug discovery. Herein we report the development of indole-based fragments that bind in a shallow surface pocket of a humanised surrogate of RAD51. RAD51 is an ATP-dependent recombinase that plays a key role in the repair of double-strand DNA breaks. It both self-associates, forming filament structures with DNA, and interacts with the BRCA2 protein through a common “FxxA” tetrapeptide motif. We elaborated previously identified fragment hits that target the FxxA motif site and developed small-molecule inhibitors that are approximately 500-fold more potent than the initial fragments. The lead compounds were shown to compete with the BRCA2-derived Ac-FHTA-NH2 peptide and the self-association peptide of RAD51, but they had no effect on ATP binding. This study is the first reported elaboration of small-molecular-weight fragments against this challenging target.read more
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TL;DR: Mechanistic studies reveal that ABT-737 does not directly initiate the apoptotic process, but enhances the effects of death signals, displaying synergistic cytotoxicity with chemotherapeutics and radiation.
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ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets
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TL;DR: The re-engineering of navitoclax is reported to create a highly potent, orally bioavailable and BCL-2–selective inhibitor, ABT-199, which inhibits the growth of BCL–dependent tumors in vivo and spares human platelets, indicating that selective pharmacological inhibition of Bcl-2 shows promise for the treatment of B CL-2-dependent hematological cancers.
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The influence of drug-like concepts on decision-making in medicinal chemistry
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The atomic structure of protein-protein recognition sites.
TL;DR: In this paper, the authors performed an analysis of the recognition sites seen in 75 protein-protein complexes of known three-dimensional structure: 24 protease-inhibitor, 19 antibody-antigen and 32 other complexes, including nine enzymeinhibitors and 11 that are involved in signal transduction.
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