# Covalent Protein Binders for Cancer Research and Therapy

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2023 · $396,134

## Abstract

Protein-protein interactions are involved in a broad range of cell function and signaling. Various protein binders
have been developed to detect or modulate such interactions for research, diagnostic, and therapeutic
applications. However, existing protein binders usually bind to their targets in noncovalent mode only, imposing
limitations on affinity, stability, and completeness. In addition, covalent bonding between a drug and its target
offers multiple desirable therapeutic properties over noncovalent interactions of conventional drugs. Such
covalent mode has been implemented in small molecule drugs with great success in recent years, yet the
therapeutic potential of covalent protein drugs remains largely untapped. To change this paradigm, this project
will develop covalent protein binders and generate covalent protein drugs. New latent bioreactive amino acids
will be designed and genetically incorporated into protein binders, which will react with a natural residue of the
target only upon protein binding, selectively creating a stable covalent linkage between the two proteins.
Covalent protein binders specific for immune-checkpoints and membrane receptors associated with cancer will
be generated. The distinct effects of these covalent protein binders on cancer cell signaling and function will be
assessed in vitro, and their cytotoxic activity and anti-tumor efficacy as covalent protein drugs will be evaluated
in xenografted mouse models. The success of this project will instigate a new dimension for researching cell
signaling and function through highly selective, stable, and covalent modulation of proteins. A general platform
technology will be established for the development of covalent protein drugs, leading to a new generation of
biotherapeutics with a fundamentally different binding mechanism for cancer treatment.

## Key facts

- **NIH application ID:** 10569518
- **Project number:** 5R01CA258300-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Lei Wang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $396,134
- **Award type:** 5
- **Project period:** 2021-03-01 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10569518

## Citation

> US National Institutes of Health, RePORTER application 10569518, Covalent Protein Binders for Cancer Research and Therapy (5R01CA258300-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10569518. Licensed CC0.

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