Science

We aim to develop best-in-class therapies for under-addressed targets and to pioneer first-in-class medicines against the historically undruggable—bringing new hope to patients across a range of devastating diseases.

What We Do

We are leveraging the power of lysine-based covalency across the disease spectrum to develop both best-in-class therapies against known drug targets and first-in-class medicines against the previously undruggable.

Our Approach

Drug Discovery and Development Engine

At Terremoto Biosciences, we have aspired to embrace innovative chemistry, advanced fragment-mapping, and iterative structure-based design to transform the treatment landscape. Terremoto was founded on the principle that covalent engagement of unique amino acids can provide access to novel drug targets and enable small molecule therapeutics with a differentiated mechanism-of-action. This strategy initially allowed us to develop an understanding of optimal ways to target proteins with a critical role in the pathogenesis of important human diseases and, ultimately, to develop impactful and differentiated therapeutics.

As our pipeline of novel therapies enter clinical trials to treat patients with cancer and vascular disorders, we aspire to develop a profound understanding of these disease states to enable novel clinical development strategies to efficiently bring drugs to patients in need. Translational approaches to assure the ideal level of target engagement to optimize dose and risk-benefit profile are critical for efficient drug development. Additionally, our clinical programs are designed to ensure we efficiently identify the patient populations who are most likely to respond to therapy utilizing precision medicine approaches and correlative sciences strategies. Ultimately, the combination of novel best-in-class therapeutics with a laser focused development approach is designed to provide a groundbreaking advancement to transform the lives of patients in need.

What are covalent medicines?

Covalent chemistry is central to our drug discovery strategy. We harness its advantages both as a powerful tool to guide discovery and, where appropriate, as the therapeutic modality itself.

By using the high energy and affinity of a covalent bond, it is possible to create small molecule compounds that are both more selective and potent against their intended target. How? Covalent therapies have enhanced inhibitory profiles that can deactivate mutated proteins for extended periods, without extended toxicity.

Importantly, this effect can be precisely tuned to fit the disease context. Such precision makes covalent compounds especially promising in oncology and certain genetic diseases, where targeting diseased proteins without disrupting healthy cellular function is essential. Covalent approaches have also made it possible to target key disease drivers that were once considered ‘undruggable,’ such as KRAS G12C.

Game-changing therapies like ibrutinib, osimertinib, and sotorasib have already demonstrated the transformative potential of covalent chemistry. At Terremoto, we’re advancing this technology even further—developing next-generation medicines with enhanced safety, precision, and efficacy for patients with serious unmet needs, while also contemplating opportunities to take novel approaches to target previously undruggable disease drivers.

This is why we are expanding the covalent drug alphabet to include amino acids such as lysine. Lysine is prolific across the proteome and present in the sequence of most protein drug pockets. Of course, its abundance also presents challenges. Covalently bonding to lysine in a targeted, selective manner is an incredibly difficult feat, due to the residue’s reactive nature and prevalence. The reactive moiety must be in the right location, the appropriate electronic state and the correct spatial orientation to properly bond.

At Terremoto, we possess the experience, platform technology and knowledge to achieve this level of chemical and biological mastery. With the recent foundational advances in lysine-targeting chemistries from our very own founding team, we can now develop novel covalent medicines in oncology and beyond.

Why lysine-targeted covalency?

At Terremoto, we utilize a combination of:

Structure-based drug design
Screening platform development
CryoEM, X-ray crystallography

Electrophilic warhead library development
Our computational discovery engine

For known targets:

We begin by redesigning existing chemical matter to form a reversible, covalent interaction with an adjacent lysine residue. We have repeatedly demonstrated our ability to optimize these molecules to generate nearly-irreversible covalent inhibitors of the intended target.

For novel targets:

We use orthogonal approaches to tether molecules to proteins, similar to the methodology used to discover Ras inhibitors. This enables us to screen targets rapidly and cost-effectively, as well as uncover novel binding pockets invisible to traditional screening efforts.

With the deep knowledge of our founders and leadership team, we have laid the foundation for rapidly transforming standard reversible inhibitors with their intrinsic limitations into highly impactful covalent molecules. Because we work from existing, well-defined chemical matter, we have the potential to deliver medicines to patients at record speed from novel compound synthesis to drug approval. This will shave years off our preclinical and clinical development plans – all with the intent of getting superior medicines in the hands of patients as soon as we possibly can.

These tools empower rapid compound design and hypothesis testing—accelerating the discovery and optimization of molecules tailored to specific diseases and patient needs.

Science

What We Do

Our Approach

Drug Discovery and Development Engine

What are covalent medicines?

Why lysine-targeted covalency?

At Terremoto, we utilize a combination of:

Structure-based drug design

Screening platform development

CryoEM, X-ray crystallography

Electrophilic warhead library development

Our computational discovery engine

For known targets:

For novel targets:

Publications and Presentations

Mutant-selective AKT inhibition through lysine targeting and neo-zinc chelation

Reversible lysine-targeted probes reveal residence time-based kinase selectivity

Discovery of Lysine-Targeted eIF4E Inhibitors through Covalent Docking

Ligand Conformational Bias Drives Enantioselective Modification of a Surface-Exposed Lysine on Hsp90

Lysine-Targeted Inhibitors and Chemoproteomic Probes

Discovery of GBT440, an Orally Bioavailable R-State Stabilizer of Sickle Cell Hemoglobin