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The Evolution of Anticancer Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Two approved anticancer agents are claimed to have been discovered through a fragment-based approach. The first is vemurafenib (ZelborafTM) that received FDA approval for the treatment of late-stage melanoma in 2011, making it the first drug developed through a fragment-based lead discovery approach to gain regulatory approval. This agent recognizes and binds to the V600E-mutated B-RAF kinase protein, a member of the B-RAF/MEK/ERK pathway, although it also has efficacy against BRAF with the less common V600K mutation. The second example is venetoclax (VenclextaTM), which was approved by the FDA in 2016 for the treatment of CLL in patients with a 17p deletion on the chromosome 17 short arm, and who have been treated with at least one prior therapy. Venetoclax is a BH3-mimetic that blocks the antiapoptotic B-cell lymphoma-2 (Bcl-2) protein, leading to the programmed cell death of CLL cells.
1D NMR WaterLOGSY as an efficient method for fragment-based lead discovery
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2019
Claire Raingeval, Olivier Cala, Béatrice Brion, Marc Le Borgne, Roderick Eliot Hubbard, Isabelle Krimm
Fragment-based lead discovery (FBLD)1,2 is maturing as an effective method for generating small molecules that modulate the activity of biological molecules, usually proteins. The central idea is to screen a small number (typically 1000 s) of low molecular weight (usually less than 250 Da) compounds against a protein target of interest, mostly using a sensitive biophysical technique that can detect binding with an affinity as weak as low mM (KD for dissociation)2–4. Hit fragments are then optimised by either growing or merging features of compounds to generate lead molecules. Such molecules can subsequently be used as tools to probe the biology of a protein or be further optimised to give clinical candidates such as the recently approved medicines, vemurafenib, and venetoclax5,6. While it is relatively straightforward to find many (100 s of) fragments that bind for most proteins7, it may be more difficult to characterise the molecular interactions within the protein-fragment complexes when X-ray crystallography is not successful. Yet the assessment of the ligand binding mode is a critical information that provides important guidance for the identification of suitable modification locations in fragment optimisation.
Antimicrobial drug discovery: lessons of history and future strategies
Published in Expert Opinion on Drug Discovery, 2018
Anthony Travis, Olga Chernova, Vladislav Chernov, Rustam Aminov
The vast genetic diversity of uncultivated microbiota in many different ecosystems is not accessible using classical microbiological techniques, but its potential for antimicrobial production can be accessed indirectly through metagenomics. Complete chemical synthesis of antimicrobials, which was pioneered by Paul Ehrlich more than a century ago [2], was modified in the late 1990s as the technique of fragment-based lead discovery. Identification of small ligands using this approach relies on the availability of pathogen genomes, development of bioinformatic tools for identification of potential targets and drug-target interactions, as well as improvements in X-ray crystallography, NMR spectroscopy, and large-scale screening systems. Small ligands identified this way may then be used to discover larger and more potent ligands. Antimicrobials could also be engineered to possess dual target activities by combining the known antimicrobials into the hybrid molecules.
Testing for drug-human serum albumin binding using fluorescent probes and other methods
Published in Expert Opinion on Drug Discovery, 2018
Michael Ronzetti, Bolormaa Baljinnyam, Adam Yasgar, Anton Simeonov
The MST technique has allowed researchers to probe the affinity of the interaction between different polyglycerol analogs to HSA, probe the binding of neonatal Fc receptor to albumin proteins, and the interaction between phycocyanobilin and bovine serum albumin [79–81]. The approach has also shown high-throughput capabilities, with researchers demonstrating the potential of MST as part of a fragment-based lead discovery program and as a triage tool during a number of different stages of the high-throughput screening workflow [82,83]. It is entirely conceivable to witness the adaptation of MST into a high-throughput workflow in monitoring the interaction between small molecule libraries and serum albumins.