Does control of proximity equal control of biology?

How mapping the ‘effectome’ allows General Proximity to develop small molecule drugs for targets once thought to be undruggable.

Earlier this year, we brought you the story of General Proximity, which emerged from stealth with $16 million to advance the development of next-generation “induced proximity” medicines. The company’s technology leverages the concept of biological proximity – the interaction or nearness of macromolecules – to precisely control molecular interactions.

General Proximity’s approach is designed to enable modulation of previously undruggable targets, including proteins and enzymes associated with disease and decline. By identifying and recreating therapeutically beneficial “proximity events” within cells, the company aims to drive chemical reactions targeting oncology, neurodegeneration and longevity.

Longevity.Technology: The concept of molecular proximity has emerged as a potentially transformative therapeutic strategy and several proximity-based therapies like PROTACs (proteolysis-targeting chimeras) are already in clinical trials. However, challenges remain – particularly in identifying the key proteins that create a desired effect. The hope is that better characterization of these cellular “effector” proteins will lead to more effective treatments. To find out more about how General Proximity intends to harness the potential of this biological phenomenon, we caught up with its founder and CEO Dr Armand Cognetta.

One of the fundamental concepts that the company is based on is that proximity is a master regulator of biology, and plays a key role in driving chemical reactions that control everything from organs down to cells and molecules.

“There are thousands of proteins in every cell in your body, which essentially serve as molecular machines to build, modify, localize and degrade other proteins,” says Cognetta. “These comprise the ‘effectome’, and they are regulated through proximity. At its root, biology is a vast dynamic interplay of these molecules being brought in and out of proximity with their targets to orchestrate life.”

Rapamycin is a proximity drug

The thesis behind General Proximity was that if it was possible to co-opt or “hijack” these same systems as therapeutic tools, then you could vastly increase the set of transformations that can be performed upon drug targets. Describing this as “one of the most critical areas of drug discovery,” Cognetta believes that “control of proximity ultimately equals control of biology.”

“Biology uses this over and over – there are just so many examples of this,” he adds. “For example, rapamycin is a proximity drug – it induces a complex of a protein called FKBP12 with mTOR to inhibit it and promote autophagy.

“Proximity is a recurring theme that has serendipitously popped up in drug discovery, and we wanted to be the first company to systematically take advantage of it to do complex transformations upon drug targets.”

When it comes to drug discovery, Cognetta says there are only two hard problems: what to drug and how to drug it.

“Once you know your target, it’s often extremely difficult to actually make a drug that that modulates the target in a way that’s useful,” he says. “And that has driven the drug discovery field to go from small molecules, which are good at breaking stuff, but very bad at doing anything more complex, to all these more complex modalities, like antibodies, gene therapies and CRISPR.”

While these more complex therapies allow drug developers to do things that are beyond the realm of traditional pharmacology, Cognetta says they also have many drawbacks.

“They’re expensive, you can’t take them orally, they don’t easily get into cells or the CNS – all sorts of challenges,” he explains. “What you really want is a drug that has the features of a small molecule – you can take it orally, it permeates through your body and it’s cheap – but also has the power to more than just break stuff. Things like refolding proteins, or activating them, or changing their function, or relocalizing them, or modulating them, or inducing a gain of function.”

Mapping the ‘effectome’

Addressing these challenges was what led biotech veteran Cognetta to found General Proximity.

“The basic idea behind forming the company was: if biology controls so much of itself by proximity, why don’t we make drugs that do this too?” he says. “What if we could repurpose the entire set of proximity tools in a cell, and use a small molecule to co-opt an existing protein in your body? That way, instead of delivering a protein, you’re just co-opting some existing tool and using that to modulate biology.”

According to Cognetta, around 10% of the human genome codes for proteins that modify other proteins – a set of proteins that General Proximity has termed the “effectome”.  

“There was no name for this set of proteins before,” he says. “It basically refers to all of the PTM proteins, readers, writers, erasers, but also things like adapter proteins, chaperone proteins, trafficking proteins, and so on. In terms of drug discovery, these represent a set of extremely powerful tools that could expand the armamentarium of what you can do in biology to things that are normally hard to drug.”

Cognetta claims that General Proximity has built the first platform that maps a drug target to the specific proximity mechanisms relating to it.

“Almost all drug targets are amenable to this approach, but which mechanism do you use – there are thousands!” he explains. “That’s the really hard question, and that’s the technology we have pioneered. So we built a bunch of different tools that allow us to understand the proximity event that best drives a therapeutic effect for a given drug target. Then we can develop small molecule drugs that recapitulate that event.”

Since building its platform “from the ground up”, General Proximity has now started using it in earnest.

“We have begun applying it for two pretty major targets we’ve discovered using the platform,” says Cognetta. “We’ve discovered proximity mechanisms that allow you to modulate the drug target in ways that are more powerful than what anyone’s been able to do in the past with any modality.”

“We’ve now taken the next step, where we’ve discovered a mechanism and made a drug, and we’re currently in the process of lead optimization for that drug to move it into the clinic,” he adds.

Significant potential in longevity

While the company is keeping its cards close to its chest for now, Cognetta refers to a number of General Proximity’s targets as being “longevity-adjacent”, in addition to its programs in neurological disease and oncology. This probably explains why Laura Deming’s Longevity Fund was one of the company’s first major investors, along with Y Combinator.

“I have always been really interested and oriented towards the longevity space,” says Cognetta. “There are so many potential applications of proximity drugs to diseases of aging. For example, one of the hallmarks of aging is proteostasis – the dysregulation or aggregation of many different types of proteins. It’s very hard to clear those with normal therapeutics, but I think that PROTACs and also what we’re doing are perfect for this type of thing.”

Modulation of transcription factors to enable cellular reprogramming is another area where Cognetta believes proximity therapeutics can play a role.

“Transcription factors are a canonically undruggable class of proteins – they’re these big floppy pieces of spaghetti that interact with big floppy pieces of DNA, and they don’t really have normal small molecule binding sites,” he says. “But we believe they are a perfect fit for our approach, because transcription factors, even more so than most other types of proteins, are all controlled by protein-protein interactions, which are proximity events. We’ve already shown some proof of concept data where we’ve been able to reprogram transcription factors with small molecules.”

“Even if you make a nice cellular reprogramming gene therapy, it’s going to be very hard to make it systemic and safe,” adds Cognetta. “I think there is a massive amount of potential in longevity to control master regulators of various aging processes with small molecules via proximity. I wouldn’t be surprised if some of the most powerful longevity therapeutics end up being small molecule proximity drugs that modulate transcription.”

Photographs courtesy of General Proximity.