Stanford Advisors

All Publications

  • A bivalent molecular glue linking lysine acetyltransferases to oncogene-induced cell death. Cell Nix, M. N., Gourisankar, S., Bowman, K. J., Nettles, S. A., Yang, H., Dwyer, B. G., Sarott, R. C., Abuzaid, H., Martinez, M. M., Phillips, N., Cabaud, V., Hakobyan, A., Arakelov, V., Petrosyan, G., Davtyan, A., Wang, Y., Simanauskaite, J. M., Romero, B. A., Jones, H. M., Krokhotin, A., Lowensohn, T. N., Chen, L., Low, C., Vogel, H., Davis, M. M., Fernandez, D., Zhang, T., Green, M. R., Hinshaw, S. M., Gray, N. S., Crabtree, G. R. 2026

    Abstract

    Developing cancer therapies that induce specific death of malignant cells is critical for preventing relapse. Highly effective strategies, such as immunotherapy, exemplify this principle. Here, we provide the mechanistic basis for a small-molecule approach that leverages chemically induced proximity (CIP) to kill diffuse large B cell lymphoma, the most common non-Hodgkin lymphoma. We developed lysine acetyltransferase (KAT)-based TCIPs (transcriptional/epigenetic chemical inducers of proximity), or KAT-TCIPs, which redirect p300/CREB-binding protein (CBP) to activate cell-death networks repressed by the oncogenic driver BCL6. Our lead KAT-TCIP reprograms the epigenome to initiate apoptosis. The crystal structure of the chemically induced p300-BCL6 complex reveals how chance protein-protein interactions may be exploited to confer the potency and selectivity of KAT-TCIPs. Thus, oncogenic drivers can be co-opted to activate robust cell death. Consistent with their gain-of-function mechanism, TCIPs recruiting different transcriptional activators-p300, BRD4, or CDK9-produce distinct genomic responses, suggesting specialized therapeutic uses.

    View details for DOI 10.1016/j.cell.2026.06.037

    View details for PubMedID 42476129

  • DNA damage chemical inducers of proximity (DD-CIP) for targeted cancer therapy Qiu, T., Lee, Y., Dwyer, B. G., Tan, Y., Chen, T., Romero, B. A., Wang, Y., Deng, J., Zhang, T., Crabtree, G. R., Hinshaw, S. M., Wong, K., Gray, N. S. AMER ASSOC CANCER RESEARCH. 2026: LB025

    View details for DOI 10.1158/1538-7445.AM2026-LB025

    View details for Web of Science ID 001744443300013

  • Hijacking the BRD4-NUT fusion oncoprotein to activate programmed cell death Wang, K., Wang, Y., Qiu, T., Dwyer, B. G., Griffin, D., Shapiro, G. I., French, C. A., Gray, N. S., Crabtree, G. R. AMER ASSOC CANCER RESEARCH. 2026

    View details for DOI 10.1158/1538-7445.AM2026-7881

    View details for Web of Science ID 001734420600045

  • Design and Development of DNA Damage Chemical Inducers of Proximity for Targeted Cancer Therapy. Journal of the American Chemical Society Qiu, T., Lee, Y. T., Dwyer, B. G., Tan, Y. J., Chen, T., Romero, B. A., Wang, Y., Deng, J., Zhang, T., Crabtree, G. R., Hinshaw, S. M., Wong, K., Gray, N. S. 2026

    Abstract

    Many chemotherapies are effective against cancers that display high levels of genome instability by disrupting or overwhelming the DNA damage response (DDR) to induce cell death. PARP inhibitors (PARPi) exploit this vulnerability by stalling DNA repair, particularly in homologous recombination-deficient cancer cells. Although PARPi are now used to treat BRCA1/2-mutated cancers such as ovarian and breast cancers, they are still limited to a narrow range of clinical indications and are susceptible to acquired resistance. Here, we introduce "DNA damage chemical inducers of proximity" (DD-CIPs), bivalent molecules that rewire the mechanism of action of conventional PARPi. The DD-CIPs function through chemically induced proximity between PARP1/2 and the chromatin remodeling protein, BRD4. From a candidate library of DD-CIPs, we identified DD-CIP1, which induces the DDR and apoptosis in cancer cells at two-digit nanomolar concentrations. Further optimization yielded DD-CIP2, which induces tumor cell death at nanomolar concentrations across diverse blood and solid cancer cells, including cancer types that are insensitive to PARPi. Using small-cell lung cancer (SCLC) as a model, we found that DD-CIP2 triggers DDR, cell cycle arrest, and apoptosis in vitro, leading to antitumor efficacy without substantial toxicity in preclinical SCLC xenograft models at well-tolerated doses. Our findings demonstrate that DD-CIPs may provide an opportunity to address the limitations of traditional PARPi and establish chemical-induced proximity as a strategy for modulating the DDR in cancer.

    View details for DOI 10.1021/jacs.5c17396

    View details for PubMedID 41480895

  • Design and Development of DNA Damage Chemical Inducers of Proximity (DD-CIP) for Targeted Cancer Therapy. bioRxiv : the preprint server for biology Qiu, T., Lee, Y. T., Dwyer, B. G., Tan, Y. J., Chen, T., Romero, B. A., Wang, Y., Deng, J., Zhang, T., Crabtree, G. R., Hinshaw, S. M., Wong, K. K., Gray, N. S. 2025

    Abstract

    Many chemotherapies are effective against cancers that display high levels of genome instability by disrupting or overwhelming the DNA damage response to induce cell death. PARP inhibitors (PARPi) exploit this vulnerability by stalling DNA repair particularly in homologous recombination (HR)-deficient cancer cells. Although PARPi are now used to treat BRCA1/2-mutated cancers such as ovarian and breast cancers, they are still limited to a narrow range of clinical indications and are susceptible to acquired resistance. Here, we introduce "DNA Damage Chemical Inducers of Proximity" (DD-CIPs), bivalent molecules that rewire the mechanism of action of conventional PARPi. The DD-CIPs function through chemical induced proximity between PARP1/2 and the chromatin remodeling protein, BRD4. From a candidate library of DD-CIPs, we identified DD-CIP1 which induces the DNA damage response (DDR) and apoptosis to a range of cancer lines at two-digit nanomolar concentrations. Further optimization yielded DD-CIP2, which induces tumor cell death at nanomolar concentrations across diverse blood and solid cancer cells, including cancer types that are insensitive to PARPi. Using small-cell lung cancer (SCLC) as a model, we found that DD-CIP2 triggers DDR, cell cycle arrest, and apoptosis in vitro, leading to anti-tumor efficacy without substantial toxicity in preclinical SCLC xenograft models at well tolerated doses. Our findings demonstrate that DD-CIPs may provide an opportunity to address the limitations of traditional PARPi and establish chemical induced proximity as a strategy for modulating the DDR in cancer.

    View details for DOI 10.1101/2025.11.03.686423

    View details for PubMedID 41278667

    View details for PubMedCentralID PMC12637661

  • Quantitative flow cytometry using quantitative streptavidin-protein G-biotin beads (qBeads). Journal of immunological methods Bharath, M., Le, A., Konda, V., Srivastava, S., Beliaev, M., Chen, M., George, A., Zhang, A., Tan, S., Ginto, E., Awatiger, A., Bahuguna, K., Li, V., Kedambadi, S., Cao, X., Zeng, H., Xiong, G., Prabhu, M., Modi, A., Wang, Y., Wang, J. 2025: 113883

    Abstract

    Quantitative flow cytometry (qFCM) is a powerful approach for the precise measurement of cellular and molecular characteristics, offering significant advantages in biomedical research, clinical diagnostics, and therapeutic applications. However, current qFCM beads, relying on chemical conjugation face several limitations. This study explored the use of streptavidin-coated beads with a defined quantity of Protein G-biotin for quantitative flow cytometry, demonstrating that these quantitative streptavidin-Protein G-biotin beads (qBeads) can be used for qFCM analysis through both direct and indirect methods, enabling the development of standardized assays for a wide range of applications.

    View details for DOI 10.1016/j.jim.2025.113883

    View details for PubMedID 40456385

  • A Bivalent Molecular Glue Linking Lysine Acetyltransferases to Oncogene-induced Cell Death. bioRxiv : the preprint server for biology Nix, M. N., Gourisankar, S., Sarott, R. C., Dwyer, B. G., Nettles, S. A., Martinez, M. M., Abuzaid, H., Yang, H., Wang, Y., Simanauskaite, J. M., Romero, B. A., Jones, H. M., Krokhotin, A., Lowensohn, T. N., Chen, L., Low, C., Davis, M. M., Fernandez, D., Zhang, T., Green, M. R., Hinshaw, S. M., Gray, N. S., Crabtree, G. R. 2025

    Abstract

    Developing cancer therapies that induce robust death of the malignant cell is critical to prevent relapse. Highly effective strategies, such as immunotherapy, exemplify this observation. Here we provide the structural and molecular underpinnings for an approach that leverages chemical induced proximity to produce specific cell killing of diffuse large B cell lymphoma, the most common non-Hodgkin's lymphoma. We develop KAT-TCIPs (lysine acetyltransferase transcriptional/epigenetic chemical inducers of proximity) that redirect p300 and CBP to activate programmed cell death genes normally repressed by the oncogenic driver, BCL6. Acute treatment rapidly reprograms the epigenome to initiate apoptosis and repress c-MYC. The crystal structure of the chemically induced p300-BCL6 complex reveals how chance interactions between the two proteins can be systematically exploited to produce the exquisite potency and selectivity of KAT-TCIPs. Thus, the malignant function of an oncogenic driver can be co-opted to activate robust cell death, with implications for precision epigenetic therapies.

    View details for DOI 10.1101/2025.03.14.643404

    View details for PubMedID 40166243

    View details for PubMedCentralID PMC11956963

  • A novel AKR1C3 specific prodrug TH3424 with potent anti-tumor activity in liver cancer. Clinical pharmacology and therapeutics He, P. n., Wang, C. n., Wang, Y. n., Wang, C. n., Zhou, C. n., Cao, D. n., Li, J. n., Bushnell, D. A., Li, Q. n., Kornberg, R. D., Xie, W. n., Wang, Z. n. 2021

    Abstract

    Overexpression of AKR1C3, an aldo-keto reductase, was recently discovered in liver cancers. In this study, an inverse correlation between AKR1C3 expression and liver cancer patient survival was observed. AKR1C3 inhibitors, however, failed to suppress liver cancer cell growth. The prodrug TH3424, which releases a DNA alkylating reagent upon reduction by AKR1C3, was developed to target tumors with overexpression of AKR1C3. TH3424 showed specific killing of liver cancer cells with AKR1C3 overexpression both in vitro and in vivo. In patient-derived mouse xenograft models, TH3424 at doses as low as 1.5 mg/kg eliminated liver tumors with no apparent toxicity. Conclusion: TH3424 is a promising drug candidate for liver cancer and other types of cancers overexpressing AKR1C3.

    View details for DOI 10.1002/cpt.2171

    View details for PubMedID 33483974