Hit-to-lead: It takes integration

So your hit clusters have been identified and validated in the earlier development process. Now what?

In the hit-to-lead phase, these hit clusters are assessed and whittled down to two or three hit series that have the best potential to develop into drug-like leads.

The hit-to-lead phase can be a time consuming and costly part of early drug development. The process relies on multiple techniques from computational modelling to animal handling, and expertise from disciplines as broad as biosciences, data science, and chemistry.

In such expansive projects, the key to successfully identifying drug leads is the true integration of expertise.

In fact, the most successful hit-to-lead projects are typically comprised of truly integrated teams who accelerate drug discovery in optimised work environments.

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Tweaking the hits

The hit-to-lead process begins with confirming that a true structure-activity relationship (SAR) exists within a number of hit series for the biological target.

One of the common challenges in this phase is determining how to optimise one property without compromising another.

For example, the absorption of a drug can typically be improved by reducing its molecular weight, but a lower molecular weight can exhibit negative impacts on its potency.

It’s therefore important to balance out these inter-reacting properties to develop therapeutics that exhibit beneficial characteristics during optimisation stages.

Early assessments of the chemical and biological properties of hit molecules are conducted to help in the selection of the most promising leads for optimisation. This process requires a range of techniques to comprehensively assess the absorption, distribution, metabolism, excretion, and toxicity properties of each hit cluster via ADMET/DMPK studies.

These experiments are predominantly performed in vitro, but early in vivo proof-of-concept work at the end of the hit-to-lead phase also provides powerful evidence for the ADMET/DMPK properties of each hit series.

From a development perspective, ADMET/DMPK studies at the hit-to-lead stage are a major determinant of drug discovery project timelines, costs and the ultimate quality of the hit molecules when they progress into the clinic.

Hit refinement

Hits become leads during SAR and ADMET/DMPK optimisation.

Part of this refinement involves creating a series of analogue compounds that can produce more potent or selective variants of the hit series that can better meet the criteria for drug optimisation.

Here, systematic iterations of the design, make, test, analyse (DMTA) cycle pop out new designed compounds that can be tested for (hopefully) improved features like better absorption or reduced hepatotoxicity.

Lead compounds are also screened in vivo for any possible off-target effects that could predict unwanted side effects.

Like all stages of the hit-to-lead phase, the hit refinement process relies on good-quality chemistry, in silico design and predictive modelling, and focused biological assay design to streamline ADMET/DMPK testing.

Often, multiple leads will be generated in the iterations of the DMTA cycle, and it’s critically important for the future success of lead optimisation stages that the entire process is underpinned by solid assay development and data interpretation.

Only then can high-quality drug leads be accelerated towards the clinic.

Integrated approaches

Successful hit-to-lead phases rely on skillsets from multiple sectors of science and computing, as well as smart, patient and business-minded decision making.

The complexity of optimising and balancing inter-reacting drug parameters means the most successful hit-to-lead projects are conducted by teams of experts who are truly integrated in the way they work.

These teams must be ‘multilingual’ in other disciplines and be in a proactive collaborative environment.

Lead candidates can then be taken swiftly – and cost-effectively – towards the clinic.

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