Expert view: Conquering late stage failures with advanced hit-to-lead techniques

Failing early in drug discovery is the primary driving force for new techniques in the hit-to-lead phase.

With the average cost of a new licensed drug reaching over $2bn, big pharma has embraced the ‘fail early and fail fast’ mantra. To improve the early failures rate, new techniques are required.

How is big pharma adopting new practices to fail faster?

The assessment of in vitro safety earlier in the drug discovery process is one major adoption that pharma and biotech companies are taking in order to fail their drugs out faster. Merck KGaA, Darmstadt, Germany, has developed a wide range of permeability, transporter, metabolism, and toxicology assays ( using ZFN KO Caco-2, SA7K, and HepaRG cell lines. These earlier ADME-Tox screens can help further narrow your pool of hit-to-lead candidates but only addresses the immediate safety aspect of the compound.

What other trends are developing?

The re-emergence of phenotypic screening as a confirmation/ secondary study has been gaining a lot of traction in recent years. Morphological changes in a cell’s response to a compound are a clear indicator of whether that compound can proceed to lead status from being a hit. Merck has designed a number of engineered cells that contain fluorescent reporters which enable robust visualisation of these changes. They also offer a custom engineering service ( for difficult-to-engineer cell lines.

Where do you see the future of hit-to-lead techniques?

Artificial intelligence holds promise in completely revolutionising drug discovery through computer-aided drug design (CADD) and in silico screening. Some companies have taken steps in this direction, such as IBM Watson using big data to identify novel drug candidates, and Merck’s virtual retrosynthesis tool, allowing chemists to evaluate reaction and synthesis pathways.

The life science business of Merck KGaA, Darmstadt, Germany operates as MilliporeSigma in the U.S. and Canada

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