Science

With our scientific approach, we have the potential to dramatically expand the universe of drug targets, as well as significantly improve upon existing medicines.

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

“A Game of Dynamic Tetris.”

What are covalent medicines?

Using the high energy and affinity of a covalent bond, it is possible to create superior small molecule medicines that are both more selective and potent against their intended target in a range of hard-to-treat diseases. How? Covalent therapies have enhanced inhibitory profiles that can deactivate mutated proteins for extended periods, without extended toxicity. This poses tremendous potential in oncology especially: By eliminating the cancer-driving culprits in tumor cells, the anti-tumor response could be enhanced and the chance of recurrence could be minimized.

We have already witnessed the power of covalent chemistry through game-changing medicines like ibrutinib, osimertinib and sotorasib. However, these drugs rely on binding to the amino acid cysteine, which is uncommon in proteins and thus severely limits the number of available targets.

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?

Drug Discovery and Development Engine

Inventing a New Kind of Covalent Medicine

With our lysine-targeted covalency platform, we pursue a wide breadth of protein targets, spanning from validated receptors to the historically undruggable. Our team of structural biologists, medicinal and modeling chemists, and chemical biologists works hand-in-hand to design the optimal molecules for patients.

Our platform approach, informed by our deep knowledge of structural biology, enables us to significantly expedite the drug discovery and development process. This foundational expertise enables us to create libraries of compounds and ultimately build treatments with the desired clinical profiles.

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.

Publications and Presentations

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

Yang, T., Cuesta, A., Wan, X. et al.

Nat Chem Biol (2022). https://doi.org/10.1038/s41589-022-01019-1

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

Cuesta A, Wan X, Burlingame AL, Taunton J.

J Am Chem Soc. 2020 Feb 19;142(7):3392-3400. doi: 10.1021/jacs.9b09684. Epub 2020 Feb 3.

PMID: 32009391

Lysine-Targeted Inhibitors and Chemoproteomic Probes

Cuesta A, Taunton J.

Annu Rev Biochem. 2019 Jun 20;88:365-381. doi: 10.1146/annurev-biochem-061516-044805. Epub 2019 Jan 11.

PMID: 30633551 Review.

Discovery of Lysine-Targeted eIF4E Inhibitors through Covalent Docking

Wan X, Yang T, Cuesta A, Pang X, Balius TE, Irwin JJ, Shoichet BK, Taunton J.

J Am Chem Soc. 2020 Mar 18;142(11):4960-4964. doi: 10.1021/jacs.9b10377. Epub 2020 Mar 4.

PMID: 32105459

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

Metcalf, Brian et al.

ACS medicinal chemistry letters vol. 8,3 321-326. 23 Jan. 2017, doi:10.1021/acsmedchemlett.6b00491

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