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Science & Research
Bridging the gap between genetics and small molecule therapeutics through a target-driven approach to the previously unexplored druggable proteome.
Our Novel Technology
Patented Hydrazine Probe Platform
Our patented hydrazine probe platform tags diverse electron-deficient functionalities that are intentionally installed into proteins for primary function.
Chemical Machinery and Proteome-Wide Scope
This essential chemical machinery is acquired from the local microenvironment, derived from vitamins and nutrients) and is not part of a protein’s primary structure. proteome-wide, enabling discovery of active enzyme targets and quantification of inhibitor engagement.
Therapeutic Applications and Discovery
This approach uniquely maps proteome-wide on-target selectivity and off-target side effects, and enables de novo discovery of novel metabolic enzymes and regulatory pathways that can be therapeutically modulated for late-stage drug development.
Research Highlights
Establishment of our founding technology
We were inspired by the chemistry found in old psychoactive drugs that exploit hydrazine pharmacophores as “hooks” in activity-based protein profiling (ABPP) probes.
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With these probes, we ask a simple question: how many proteins in human cells carry hidden electron-deficient features that we can covalently capture, perturb and drug?​
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Traditionally, ABPP has focused on electrophilic probes that capture nucleophilic amino acids. In contrast, our reverse-polarity ABPP (RP-ABPP) platform uses nucleophilic probes to “fish out” anything functionally electron-deficient.
This unbiased screen in native biological systems (e.g. live cells, tissues) revealed previously unrecognized electrophilic sites that fell under the radar of genetics-based prediction.
This led to the discovery of the first example of a naturally-occuring, enzymatically installed N-terminal glyoxylyl (Glox) cofactor found in a protein (Nat. Chem., 2017). And, it’s an unexpected pharmacological target of an FDA-approved psychoactive CNS drug – phenelzine.
This system is a flagship example of how we exploit chemistry for de novo discovery to uncover new biology, pathways, and therapeutic targets.
We extended RP-ABPP beyond cultured cells into tissues and in vivo mouse models. We use hydrazine drug–inspired probes to uncover the targets and mechanisms of drugs whose actions are only partially understood (Mol. Cell. Neurosci., 2023).
In parallel, we develop potent and selective inhibitors against electrophilic enzymes and hydrazine-sensitive drug targets, thereby improving the safety and efficacy of existing drugs and serve as precision tools to dissect physiological function and therapeutic potential.
The platform deploys a chemical toolbox of discovery probes and specific inhibitors for basic science and translational drug discovery in a truly new small molecule and target space(J. Am. Chem. Soc., 2022).
Deorphanized ~70year old drug for new disease indications
Hydralazine (HYZ) is one of the oldest vasodilators developed ~70 years ago as an anti-malarial. Initial evaluation in the clinic revealed that HYZ unexpectedly lowered the blood pressure of patients and was serendipitously repurposed as an anti-hypertensive.
Even today HYZ has secured its place on the World Health Organization’s list of essential medicines for the clinical treatment of hypertensive crisis and (pre)eclampsia.
Despite extensive study, HYZ’s direct target(s) and mechanism of action were entirely unknown. Employing our technology named reverse-polarity activity-based protein profiling (RP-ABPP), we identified 2-aminoethanethiol dioxygenase (ADO)—a mediator of N-degron–dependent protein degradation and sulfur-amino-acid oxidation—as a selective HYZ target. HYZ chelates ADO’s metallocofactor and can alkylate a coordinating ligand, inactivating the enzyme.
This stabilization of RGS4/5, normally marked by ADO for proteolysis, offers a mechanistic basis for vasodilation and aligns with diminished RGS levels in clinical preeclampsia and a corresponding mouse model. ADO inhibition also suggested repurposing HYZ for glioblastoma (GBM); indeed, a single dose induces robust senescence in cultured GBM cells (Sci. Adv., 2025).
By establishing ADO as a nexus between GBM and preeclampsia and linking it to HYZ, these findings open avenues to rationally tailor an old drug for new indications.
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