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Drugging the undruggable: how do we put next generation targets within our reach?

What pharmaceutical design strategies must we adopt if we’re to drug the ‘undruggable’ 80% of protein targets thought to be out of reach of current drug discovery techniques? Industry leaders from biotech and pharma gathered at The Marker Hotel, San Francisco, to discuss how to overcome this challenge at Aptuit’s interactive workshop Mission Possible: Drugging the Undruggable, held on September 18th 2017.

Not undruggable, just undrugged?

Drugging the undruggable: how do we put next generation targets within our reach?Advances in our understanding of the human genome over the past two decades have revolutionized the way we approach target discovery. Genomics-based target identification has uncovered a wealth of structural proteins and transcription factors with the potential to modify the biological processes responsible for diseases such as cancer and dementia, affecting growing numbers of patients worldwide.

While traditional medicinal chemistry has focused on disrupting cellular pathways by drugging protein ligand binding or allosteric sites using small molecules or biologics, the majority of these next generation targets cannot be modulated through ‘lock and key’ models. Instead, interrupting the protein–protein interactions of these targets may be the best way to control their function – an approach that falls outside of pharma’s usual comfort zone.

However, as Alexey Bazarov, Founder of Meristem Biotech Consulting and session chair points out, druggability should never be seen as an impossible challenge. Three decades ago, targets such as protein kinases were considered out of reach of medicinal chemists. Today, around 20 percent of all industrial research programs are focused on these targets, with kinase inhibitors central in the treatment of several forms of cancer. So, how do we accelerate progress for today’s ‘undruggable’ targets?

New drug discovery strategies

With disrupting protein–protein interactions being key to modulating these targets, the general consensus is that the most effective drugs should combine the versatile surface recognition and high target specificity of biologics with the synthetic tractability of small molecules. In other words, we need to broaden our search of chemical space.

To do this, many argue that we need to adopt new approaches to drug discovery. In the words of keynote speaker Simone Braggio, Vice President and Head of Drug Design and Discovery at Aptuit, “by following the same processes, using the same tools and screening libraries, you’ll find the same ineffective solutions.”

So what approaches should we adopt? While classical approaches based on high throughput screening may still be effective for some targets, for those where limited information is known about structure and function, structural biology could be a good place to start. Fragment based screening approaches, coupled with the latest assay detection methods such as protein NMR and surface plasmon resonance that can more finely probe the structural changes associated with the disruption of proteinprotein interactions, look set to play an increasingly important role in drug discovery.

Much of the day’s discussion focused on the design of compound screening libraries, where many feel we’ve been too narrow in our outlook. A broader focus on natural products and macromolecules, currently underrepresented in compound screening collections, may open up new areas of chemical space and could accelerate the discovery of innovative therapies.

Another focus point was the need to consider alternative routes of administration. Pharma’s traditional focus on oral bioavailablility has driven drug design towards hydrophobic molecules. But with hydrophilic molecules thought to be more effective at disrupting proteinprotein interactions, do we need to get better at solving oral bioavailability issues, or should we challenge the oral delivery dogma and more routinely consider parenteral approaches?

Sharing knowledge and building bridges

While much of the discussion was focused on new technologies and drug discovery strategies, a common theme throughout the event was that more could be achieved through greater collaboration.

One of the key discussion points was the idea that the sharing of pre-proprietary knowledge, such as information on non-progressed targets or genomics data, is necessary to better understand the challenges facing the field. Combined with effective data mining approaches, this information could, for example, lead to a collective focus on the most promising targets or the development of more effective animal models. With suitable data protection safeguards in place, and under the custodianship of a neutral non-profit organization, this information could potentially accelerate the drug discovery process for the benefit of all.

Perhaps the first step towards this goal is to build bridges between organizations and make an integrated approach to drug discovery routine within the industry. “We need to encourage collaborations, not just between organizations and academic groups – but within companies too,” says Irene Choi, Director of Drug Discovery at Verge Genomics.” Here, it’s all about looking beyond our own knowledge space, and putting the pieces of the puzzle together to accelerate progress.

So, will we be able to drug the targets currently out of reach? Like many others, Julia Schaletzky, Associate Director at Cytokinetics, is confident that through technological advances, innovative strategies and collaborative working, we will be able to make this a reality. “With so many truly innovative drug discovery approaches being put into practice, I’m optimistic that the biotech and academic ecosystem will, in time, be able to tackle these important challenges.”

Mission Possible: Drugging the Undruggable provoked much discussion around the strategies and technologies we’ll need to adopt if we’re to deliver innovative therapies for unmet diseases. The event comes to San Diego on November 5th and 6th 2017. We’d be delighted to see you there!

Topics: Drug Development