General Proximity (@proxbio) is coming out of stealth.
General Proximity is developing a new class of medicines that we believe has the potential to decrease global disease burden, transform human health, and extend lifespan more than any other current therapeutic modality. 🧵
General Proximity is developing a new class of medicines that we believe has the potential to decrease global disease burden, transform human health, and extend lifespan more than any other current therapeutic modality. 🧵
General Proximity (GP) is a drug discovery platform company built to fundamentally re-imagine how our medicines work.
We develop treatments for the most widespread, important, and "undruggable" diseases in human health.
We develop treatments for the most widespread, important, and "undruggable" diseases in human health.
We're developing a modality called 'next-gen induced proximity medicines’.
This modality is the only technology on the horizon that (among many other things) enables broad and systemic re-programming of transcription—a process at the root of all human health and disease.
This modality is the only technology on the horizon that (among many other things) enables broad and systemic re-programming of transcription—a process at the root of all human health and disease.
A little about our technology.
GP was founded on a simple, first principles premise:
Proximity is inarguably a key regulator of biology and all major disease processes.
Yet only a minuscule fraction of existing drugs work through proximity.
GP was founded on a simple, first principles premise:
Proximity is inarguably a key regulator of biology and all major disease processes.
Yet only a minuscule fraction of existing drugs work through proximity.
We believe there's a better way to make drugs.
Manipulating proximity gives unprecedented ability to make biology behave as you wish.
Control of proximity = control of biology.
Manipulating proximity gives unprecedented ability to make biology behave as you wish.
Control of proximity = control of biology.
Why is this so important?
There are many well-known, as well as newly discovered, drug targets (aka "undruggables") where we have strong evidence they are disease causing, but where we simply lack the technology to modulate them effectively in humans.
Proximity solves this.
There are many well-known, as well as newly discovered, drug targets (aka "undruggables") where we have strong evidence they are disease causing, but where we simply lack the technology to modulate them effectively in humans.
Proximity solves this.
https://x.com/armandcognetta/status/1866259898734199163
How?
~10% of your genome codes for proteins that modify other proteins.
At GP we call this the 'effectome'. The effectome is made up of all post-translational modification (PTM) proteins (readers/writers/erasers), as well as chaperone, adaptor, and trafficking proteins.
~10% of your genome codes for proteins that modify other proteins.
At GP we call this the 'effectome'. The effectome is made up of all post-translational modification (PTM) proteins (readers/writers/erasers), as well as chaperone, adaptor, and trafficking proteins.
The effectome contains all the molecular machines (proteins and enzymes) that make biology happen.
How does nature orchestrate all the diverse effects the effectome is responsible for?
Through proximity.
An enormous amount of biology is driven by bringing biomolecules together
How does nature orchestrate all the diverse effects the effectome is responsible for?
Through proximity.
An enormous amount of biology is driven by bringing biomolecules together
At GP we've built the first platform technology that allows for broad, unbiased, phenotypic-first screening across the effectome to discover novel proximity-based mechanisms.
These insights can then be used to make induced proximity medicines for previously "undruggable" targets
These insights can then be used to make induced proximity medicines for previously "undruggable" targets
What targets?
Our internal pipeline can be fully summed up just in two words:
Moonshots only.
(This isn't the only way to run a platform company, just my personal favorite.)
Our internal pipeline can be fully summed up just in two words:
Moonshots only.
(This isn't the only way to run a platform company, just my personal favorite.)
As mentioned above, re-programming human transcription is one of our core R&D areas.
Transcription factors (TFs) are one of the canonically "undruggable" classes of targets. This is because they often:
-have no evolved small-molecule binding sites
-are intrinsically unstructured
Transcription factors (TFs) are one of the canonically "undruggable" classes of targets. This is because they often:
-have no evolved small-molecule binding sites
-are intrinsically unstructured
If DNA is the code of the human body, TFs are the programs. They orchestrate which of our ~20k genes are expressed at any given time.
TFs dynamically mediate a cell's response to basically all biological inputs: stress, DNA damage, nutrient levels, inflammation, immunity, etc.
TFs dynamically mediate a cell's response to basically all biological inputs: stress, DNA damage, nutrient levels, inflammation, immunity, etc.
Want new mitochondria? A drug that mimics fasting or exercise? To regenerate a damaged organ? To repair broken DNA? To create new stem cells? To activate your body's natural anti-tumor defenses?
All of these processes, and many more, are driven by transcription.
All of these processes, and many more, are driven by transcription.
Why do TFs have such good platform-disease fit for us?
Besides being extremely important, hard-to-drug targets, TFs have another unique feature:
Even more so than other proteins, they are tightly regulated through proximity interactions.
Besides being extremely important, hard-to-drug targets, TFs have another unique feature:
Even more so than other proteins, they are tightly regulated through proximity interactions.
Physiologically, TF activity is often tuned by symphonies of hundreds of PTMs and thousands of other proximity events.
GP's thesis is that because of this it's likely much easier to control TF activity through proximity, but also that the best effector proteins to achieve a desired effect are usually completely non-obvious.
Hence our unbiased, effectome-wide, phenotypic screening platform.
Hence our unbiased, effectome-wide, phenotypic screening platform.
Another major challenge of TFs is that they are often natively unligandable due to lack of binding pockets and secondary structure.
However, when TFs complex with other proteins, they often gain structure as well as druggable binding sites at the TF/effector protein interface.
However, when TFs complex with other proteins, they often gain structure as well as druggable binding sites at the TF/effector protein interface.
This is one other major area where our platform shines.
By searching through effector space we can discover proximity mechanisms that both a) tune the TF in any way we wish and b) form a druggable complex with the TF.
By searching through effector space we can discover proximity mechanisms that both a) tune the TF in any way we wish and b) form a druggable complex with the TF.
The potential benefit for patients here is huge. We're currently working in neurodegeneration, oncology, cardiometabolic diseases, and longevity, all areas with massive unmet medical need, and where re-programming TFs or other "undruggable" targets could be game-changing.
It's also worth repeating that because our therapies are small-molecule based, they have the potential for systemic and CNS penetrance, so can access targets and organs currently beyond the reach of other next gen modalities like CRISPR, mRNA, biologics, and gene therapies.
Just one small sneak peek of some of our data. Below is one of our earlier high-throughput TF re-programming screens. We were able to demonstrate both proximity-mediated inhibition and activation of a well-known "undruggable" TF through proximity.
Importantly, the effects were actually much more nuanced than eg simple activation, and we were able to subsequently demonstrate activation of specific subsets of the genetic programs this TF is responsible for.
A little bit more about me and the company.
I'm driven by two core motivations:
1/ the love of scientific curiosity and belief that its pursuit can change the world for the better
2/ a deep belief that failure to solve the problems we are working on will lead to unnecessary suffering for the people I love and millions of others.
1/ the love of scientific curiosity and belief that its pursuit can change the world for the better
2/ a deep belief that failure to solve the problems we are working on will lead to unnecessary suffering for the people I love and millions of others.
Importantly, the tech we're developing at its core is small-molecule based, with all the long-term societal benefits thereof:
-cheaper to make/ship
-easier to deliver (oral bioavailability, systemic penetrance)
-much cheaper than biologic/genetic therapies, esp when off patent.
-cheaper to make/ship
-easier to deliver (oral bioavailability, systemic penetrance)
-much cheaper than biologic/genetic therapies, esp when off patent.
We're also well positioned to take advantage of the increasing tailwinds of AI for small-molecule drug discovery. In the next ~decade it will likely be possible to design potent, selective, druglike small molecules for nearly any target of interest with the click of a few buttons
The high-throughput data sets of proximity interactions our platform generates will allow us to go beyond this however, and build the first foundational models for the generative small molecule design of induced proximity medicines.
Drug discovery is *extremely hard*. We've accomplished a huge amount in the time we've existed but we still have many more hurdles to overcome before our drugs can begin improving the lives of patients.
It's been the journey of a lifetime so far though.
writing.arman.do/p/some-things-…
It's been the journey of a lifetime so far though.
writing.arman.do/p/some-things-…
As with any scientific endeavor we are extremely lucky to stand on the shoulders of giants who have brought the field to a point where our goals have begun to become possible.
To name just a very few: @CraigMCrews, Ray Deshaies, and @SchreiberStuart have laid the ground work in the proximity space with TPD and beyond.
To name just a very few: @CraigMCrews, Ray Deshaies, and @SchreiberStuart have laid the ground work in the proximity space with TPD and beyond.
My PhD work with Benjamin Cravatt was foundational for me and helped set my quality bar very high.
I was also lucky to start my biotech career many years ago as an intern at @Alnylam, which indelibly stamped my soul with a love and appreciation for the power of platform cos.
I was also lucky to start my biotech career many years ago as an intern at @Alnylam, which indelibly stamped my soul with a love and appreciation for the power of platform cos.
Internally we are very lucky to be advised by some of the greats as well, with people like Andy Crew (first employee/former CTO of @ArvinasInc), Larry Hamann (ex-Takeda, Celgene, BMS, Novartis exec), Martin Babler (exited Principia CEO and founder of Alumis), and many others.
I also get to work with real-life superheroes every day. GP's team is made up of a phenomenal group of scientists who collectively have done things which, previously, were quite literally impossible.
generalproximity.bio/team
generalproximity.bio/team
Everyone tells you when you start a company that recruiting great people is the single most important thing you can do, but it turns out that even if you believe this it's still possible to underweigh its significance by an order of magnitude or more.
https://x.com/armandcognetta/status/1861876887783448664
We've also been fortunate to win a record number of big pharma Golden Ticket awards from @bmsnews, Astellas, Ono Pharma, Servier, and @abbvie. whose advice and resources have been priceless.
GP is also a @JNJNews @JLABS company, and benefits enormously for J&J's expertise.
GP is also a @JNJNews @JLABS company, and benefits enormously for J&J's expertise.
In total GP has now raised $16M across pre-seed/seed and non-dilutive funding.
Our recent over-subscribed $8M seed round was led by @asenkut at @felicis.
Some of our other investors include @ycombinator, @wilsonsonsini, @LauraDeming (@age1vc), and @sahirali (Modi Ventures).
Our recent over-subscribed $8M seed round was led by @asenkut at @felicis.
Some of our other investors include @ycombinator, @wilsonsonsini, @LauraDeming (@age1vc), and @sahirali (Modi Ventures).
As well as top angels like @8enmann (co-author GPT-3, co-founder @AnthropicAI), @JeffDean (head of Google AI), @martintrevor_ (founder @mammothbiosci), @urilopatin (YC, @khoslaventures), @kanjun (founder @imbue_ai), @alectricity (@AsimovBio), and Sarah Constantin (ex-Recursion).
GP has also recently been awarded $3.4 M in non-dilutive funding from amazing institutions like @ARPA_H and @theNCI.
https://x.com/armandcognetta/status/1849889354447192477
We've been extremely lucky to have such an amazing and diverse group investors cheering us on every step of the way.
One day I'll share more of the full founding journey of GP, but tl;dr it's been quite a ride!
One day I'll share more of the full founding journey of GP, but tl;dr it's been quite a ride!
https://x.com/armandcognetta/status/1767969850192965797
Thanks for reading!
You can learn more and follow our journey at:
Nothing is undruggable.generalproximity.bio
You can learn more and follow our journey at:
Nothing is undruggable.generalproximity.bio
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