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Hacking the Human Cell – How Once ‘Un-druggable’ Proteins Became the New Frontier in Drug Development

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By Jonathan Montagu, CEO and founder of HotSpot Therapeutics, as part of the From The Trenches feature of LifeSciVC.

White Hat Hackers, sometimes called “ethical hackers,” are individuals that work to find and fix security problems in a system by exploiting its entry points. They don’t use their computers like the rest of us do. While most of us start our workdays by firing up a laptop, clicking a web browser icon and moving through a series of user-friendly, color-coded steps, white hat hackers spend their days looking at black screens strewn with code that seems unintelligible to the untrained eye. It’s as if they are getting behind the screen, peering deep inside the inner workings of the computer where they can unlock secret functions and reprogram conventional behaviors.

Until recently, small molecule drug discovery operated a lot like the typical computer user. Researchers would target the active site on a protein where small molecules can bind and inhibit a chemical reaction. Much like clicking into Chrome or Safari and navigating to a website, traditional drug discovery tools targeting catalytic sites drive predictable cellular responses. And, much like the typical web browser, they only scratch the surface of what’s possible when we unlock the full power of technology to push beyond the obvious to the uniquely differentiated.

Hacking Protein Hot Spots

The fact is, we have long known that there is a lot more to protein function than just the active site. Researchers have been working for decades to unlock the functional pockets on proteins beyond the active site that control cell function, but they are notoriously elusive. Matching these functional pockets, or natural hotspots, on the cell with the right chemical compounds to drive a desired outcome has been even more challenging because scientists have had a limited, one-dimensional view of cell structure focused squarely on the active site. For that reason, most breakthroughs that have gone beyond the active site have been stumbled into accidentally.

HotSpot Therapeutics was built on the realization that these natural hotspots can, in fact, be targeted and drugged if we start thinking more like ethical hackers. We closed a Series C financing several months ago with the explicit goal of turning molecules that bind to natural hotspots into potential medicines.

Thanks to advances in protein analytics, computer modeling, and machine learning technologies, it is possible for today’s drug hunters to unlock their inner hackers. In fact, by using our Smart Allostery™ platform, which uses cutting-edge computer algorithms to identify functional pockets on proteins, we have been able to identify over 1,500 proteins with putative switch mechanisms.

We believe our approach is unique in the diversity of advantages it offers for developing novel and differentiated orally bioavailable medicines.  Due to the key role natural hotspots play in driving cellular protein function, these molecular on/off switches can be used to transform protein activity with innate selectivity.  Moreover, the opportunity to exploit new biological real estate potentially opens up huge opportunities to take control of the cell to drive a desired effect.

Taking Control of Immune Response

Take CBL-B, for example, which acts as a gatekeeper in immune cell activation, and has become the subject of a great deal of enthusiasm in the clinical community as a prime target for therapeutic intervention. While there is no direct clinical validation of CBL-B as yet, the pharmacodynamic effects driven by CBL-B inhibition that have been observed in preclinical studies have been strongly associated with improved clinical outcomes.

Signals from our preclinical data working with CBL-B have shown that hotspot targeting makes it possible to inhibit the negative regulatory functions of the protein coding gene that serves as a master regulator, effectively lowering the threshold for T cell and NK cell activation and reducing the susceptibility of those cells to suppression inside a tumor. Put simply, by taking control of the natural hotspot of CBL-B, we’ve been able to selectively activate a targeted immune response inside a tumor that is trying to shut it down. That’s a level of precision and control that is generally not possible in the world of traditional active site target drug development.

Even better, through continual refinement of our algorithms, we’re able to identify all pockets within a protein subclass, annotate them for their regulatory function, assess them qualitatively and quantitatively for their ligandability, and cluster those that have co-evolved across the target class. Going back to the computer hacking metaphor, this is akin to not only hacking into one machine but identifying the repeating patterns and behaviors that make it possible to hack into every computer in the cluster.

Redefining Drug Discovery

And that’s just the beginning.  As we prepare to enter the clinic, we believe this same approach will make it possible to further refine the target patient population, digging into the specific immune and genomic structures of individual patients and using their unique immune and genomic signatures to define key patient subsegments.

For better or worse, advances in technology have made it possible to unlock doors that have never been opened before to look deeper into the inner workings of our world than ever before possible. To quote Amy Webb, a leading futurist and business advisor, “the biggest and the most durable inventions of the 21st century are going to be at the nexus of biology and technology.” While computer hacking is hardly the highest calling for this new capability, computational technology leveraging many of the same concepts and processes could be the key to rooting out disease as we know it.

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  • Source: https://lifescivc.com/2022/06/hacking-the-human-cell-how-once-un-druggable-proteins-became-the-new-frontier-in-drug-development/?utm_source=rss&utm_medium=rss&utm_campaign=hacking-the-human-cell-how-once-un-druggable-proteins-became-the-new-frontier-in-drug-development

This Post was originally published on Life SciVC

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