Contact

  • Academic
    xijun@stanford.edu
    University - Student Department: Chemistry Position: Graduate

Additional Info

  • Mail Code: 5080

All Publications

  • Activating p53Y220C with a Mutant-Specific Small Molecule. bioRxiv : the preprint server for biology Zhu, X., Byun, W. S., PieÅ„kowska, D. E., Nguyen, K. T., Gerhartz, J., Geng, Q., Qiu, T., Zhong, J., Jiang, Z., Wang, M., Sarott, R. C., Hinshaw, S. M., Zhang, T., Attardi, L. D., Nowak, R. P., Gray, N. S. 2024

    Abstract

    TP53 is the most commonly mutated gene in cancer, but it remains recalcitrant to clinically meaningful therapeutic reactivation. We present here the discovery and characterization of a small molecule chemical inducer of proximity that activates mutant p53. We named this compound TRanscriptional Activator of p53 (TRAP-1) due to its ability to engage mutant p53 and BRD4 in a ternary complex, which potently activates mutant p53 and triggers robust p53 target gene transcription. Treatment of p53Y220C expressing pancreatic cell lines with TRAP-1 results in rapid upregulation of p21 and other p53 target genes and inhibits the growth of p53Y220C-expressing cell lines. Negative control compounds that are unable to form a ternary complex do not have these effects, demonstrating the necessity of chemically induced proximity for the observed pharmacology. This approach to activating mutant p53 highlights how chemically induced proximity can be used to restore the functions of tumor suppressor proteins that have been inactivated by mutation in cancer.

    View details for DOI 10.1101/2024.10.23.619961

    View details for PubMedID 39554093

    View details for PubMedCentralID PMC11565735

  • Proteomics-Based Discovery of First-in-Class Chemical Probes for Programmed Cell Death Protein 2 (PDCD2). Angewandte Chemie (International ed. in English) Ji, W., Byun, W. S., Lu, W., Zhu, X., Donovan, K. A., Dwyer, B., Che, J., Yuan, L., Abulaiti, X., Corsello, S. M., Fischer, E. S., Zhang, T., Gray, N. S. 2023: e202308292

    Abstract

    Chemical probes are essential tools for understanding biological systems and for credentialing potential biomedical targets. Programmed cell death 2 (PDCD2) is a member of the B-cell lymphoma 2 (Bcl-2) family of proteins, which are critical regulators of apoptosis. Here we report the discovery and characterization of 10e, a first-in-class small molecule degrader of PDCD2. We discovered PDCD2 degrader by serendipity using a chemical proteomics approach in contrast to the conventional approach for making bivalent degraders starting from a known binding ligand targeting the protein of interest. Using 10e as a pharmacological probe, we demonstrate that PDCD2 functions as a critical regulator of cell growth by modulating the progression of the cell cycle in T lymphoblasts. Our work provides a useful pharmacological probe for investigating PDCD2 function and highlights using chemical proteomics to discover selective small molecule degraders of unanticipated targets.

    View details for DOI 10.1002/anie.202308292

    View details for PubMedID 37658265

  • Structure-Based Design of Y-Shaped Covalent TEAD Inhibitors. Journal of medicinal chemistry Lu, W., Fan, M., Ji, W., Tse, J., You, I., Ficarro, S. B., Tavares, I., Che, J., Kim, A. Y., Zhu, X., Boghossian, A., Rees, M. G., Ronan, M. M., Roth, J. A., Hinshaw, S. M., Nabet, B., Corsello, S. M., Kwiatkowski, N., Marto, J. A., Zhang, T., Gray, N. S. 2023

    Abstract

    Transcriptional enhanced associate domain (TEAD) proteins together with their transcriptional coactivator yes-associated protein (YAP) and transcriptional coactivator with the PDZ-binding motif (TAZ) are important transcription factors and cofactors that regulate gene expression in the Hippo pathway. In mammals, the TEAD families have four homologues: TEAD1 (TEF-1), TEAD2 (TEF-4), TEAD3 (TEF-5), and TEAD4 (TEF-3). Aberrant expression and hyperactivation of TEAD/YAP signaling have been implicated in a variety of malignancies. Recently, TEADs were recognized as being palmitoylated in cells, and the lipophilic palmitate pocket has been successfully targeted by both covalent and noncovalent ligands. In this report, we present the medicinal chemistry effort to develop MYF-03-176 (compound 22) as a selective, cysteine-covalent TEAD inhibitor. MYF-03-176 (compound 22) significantly inhibits TEAD-regulated gene expression and proliferation of the cell lines with TEAD dependence including those derived from mesothelioma and liposarcoma.

    View details for DOI 10.1021/acs.jmedchem.2c01548

    View details for PubMedID 36946421