Fragment Screen to Market Approval

Here ( is a landmark announcement from the FDA approving a new drug, Venclexta, for the treatment of patients with chronic lymphocytic leukaemia (CLL). Venclexta (Venetoclax) is a first in class BCL-2 inhibitor, but it is no ordinary small molecule. Not only is it the first example of a small molecule inhibitor of a protein-protein interaction designed from a fragment screen to reach FDA approval, but it also possesses physicochemical properties a long way from classical Lipinski space for an oral drug. This recent article in Nature reviews ( provides a timely perspective on translating studies on the mechanisms of cell apoptosis into novel chemotherapeutics, and the challenges facing the drug discovery project team at AbbieV to bring Venetoclax to the market.

Clinical data for ABT-263, an earlier first generation inhibitor, was reported in 2010. Much has been published about the discovery of ABT-263, but it is still worth reflecting on the many achievements of the drug discovery team. With its origins in early fragment based drug discovery, the work stands as an unrivalled example of the power of fragment screening.


The molecule was assembled from linking together two small fragments in proximal ligand binding sites that were identified from a pioneering 15N HSQC NMR fragment screen of a 10,000 fragment library. The hits had weak affinity that could not be measured by biochemical assays, so the team pioneered the use of NMR to develop structure activity relationships for fragment optimisation. The work culminated in the discovery of ABT-737 and then finally after further optimisation, ABT-263. It is fascinating to see the guidelines for discovering orally bioavailable drug candidates to be so completely disregarded; a Mw of 974, a Log P of <<5, three basic centres, an aniline, two sulfonyl groups including an acyl sulphonamide and a phenyl thiol.  The acidity of the acyl sulphonamide should further impede permeability, though this may be tempered by the existence of a zwitterionic species formed from the morpholine and piperazine groups. Surely a compound with this profile would struggle to penetrate the lipid membranes of cells, let alone permeate the GI tract and survive oxidative metabolism in the liver! Surprisingly the compound has potent cellular activity, albeit several fold lower than the activity measured in the biochemical assay. But not only that, the compound achieved a successful clinical outcome in phase I human trials in respect to compound exposure and clinical efficacy.

Unfortunately, not everything went the teams way. Dose limiting toxicity of Navitoclax (ABT-236) prevented escalation to levels of exposure required for maximal efficacy. The compound is unselective against BCL-XL, another member of the BCL family highly expressed in platelets and crucial for their survival. Preclinical studies highlighted the potential of thrombocytopenia caused by BAX and BAK mediated platelet cell death that was confirmed in clinical studies, with the MTD limited to substantially below the predicted efficacious dose. After 25 years of research the team had to go back to the drawing board and design a selective BCL-2 inhibitor over BCL-XL.

This would seem a daunting task but for a fascinating observation in the X-ray crystal structure of a close analogue of ABT-263. The work published in this nature paper ( shows the X -ray crystal structure of an analogue of ABT-263 bound to BCL-2 with an intercalating tryptophan (shown in purple) from a neighboring BCL-2 molecule undergoing a p-p stacking interaction with the aryl sulfonamide, while at the same time hydrogen bonding to an aspartic acid residue. Essential to the observation was that the aspartic acid was one of thedarren few residues that differed between BCL-2 and BCL-XL, with the latter having a glutamic acid. The strategy was to attach the indole to the scaffold in such a position as to mimic the intercalating tryptophan on the X-ray crystal structure with the hope of achieving selectivity. Incredibly this was achieved with an azaindole linked via an ether to the central benzamide ring to give ABT-199 that was 1000 fold selective for BCL-2 over BCL-XL in a TR-FRET completion binding assay, albeit reducing to 65 fold in a cellular assay.

ABT-199 was granted break through therapy designation in 2015. In fact the compound was so efficacious in the phase I clinical trial that apoptotic cell death of cancer cells lead to tumour lysis syndrome in some patients, so the dose escalation schedule had to be adjusted to slow the onset of the drug.

The FDA approval brings to the market a first in class medicine to CLL patients that directly targets the apoptotic programme. Of the many achievement of this programme, it is the bravery of the medicinal chemists to push against all the boundaries, guidelines and rules in drug design and yet still reach market approval that gets my admiration. If anything, it clearly emphasises that there are no rules in the design of new drugs, just guidelines.

Blog writted by Darren Le Grand


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