Meredith Nix

All Publications

• A druggable redox switch on SHP1 controls macrophage inflammation. Nature chemical biology Ng, M. Y., Nix, M. N., Du, G., Davidek, I., Burger, N., Shin, S., Toenjes, S., Takeda, H., Cheah Xin Yan, M., Zhang, B., Xiao, H., Wei, S. M., Seo, H. S., Dhe-Paganon, S., Wales, T. E., Engen, J. R., Mills, E. L., Che, J., Zhang, T., Gray, N. S., Chouchani, E. T. 2026

  Abstract

  Immunological proteins are major disease targets, yet most remain undrugged. Post-translational redox modification of cysteine residues has emerged as an important mode of immune cell regulation, particularly in macrophage cytokine responses. Here we develop a strategy for systematic discovery and small-molecule functionalization of redox-regulated cysteines on immunological proteins. Using deep redox proteomics, we annotate 788 in vivo redox-regulated cysteines across diverse immune-relevant protein domains. We demonstrate how these sites enable cysteine-directed pharmacology through discovery of a novel cysteine activation site on the immune regulator SHP1. Targeting C102, we develop a highly selective covalent agonist, SCA, which binds the N-SH2 domain to relieve autoinhibition and activate SHP1. In mouse and human macrophages, SCA selectively engages SHP1 C102, antagonizing interleukin-1 receptor-associated kinase signaling and lipopolysaccharide-induced proinflammatory cytokine production. Together, this work identifies a druggable cysteine redox switch controlling macrophage cytokine responses and provides a compendium of redox-regulated sites for therapeutic development.

  View details for DOI 10.1038/s41589-026-02163-8

  View details for PubMedID 41820548

  View details for PubMedCentralID 11026845

• Linking chromatin modifiers to cell death: gain-of-function small molecules to drug oncogenic transcription Gourisankar, S., Krokhotin, A., Ji, W., Sarott, R., Karim, B., Nix, M., Green, M., Crabtree, G., Gray, N. ELSEVIER. 2025

  View details for DOI 10.1016/j.jbc.2025.108759

  View details for Web of Science ID 001516992500080

• 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

• Rewiring Cancer Drivers to Induce Apoptosis By Transcriptional Chemical Inducers of Proximity in Chronic Lymphocytic Leukemia Han, W., Bhattacharya, A., Ji, W., Karim, B. A., Sarott, R. C., Nix, M., Gourisankar, S., Krokhotin, A., Sinha, S., Wang, Z., Shanafelt, T. D., Parikh, S. A., Gray, N. S., Crabtree, G. R., Kay, N. E. ELSEVIER. 2024: 4606-4607

  View details for DOI 10.1182/blood-2024-203582

  View details for Web of Science ID 001416841400006

• Discovery of electrophilic degraders that exploit SNAr chemistry. bioRxiv : the preprint server for biology Zhuang, Z., Byun, W. S., Kozicka, Z., Dwyer, B. G., Donovan, K. A., Jiang, Z., Jones, H. M., Abeja, D. M., Nix, M. N., Zhong, J., Słabicki, M., Fischer, E. S., Ebert, B. L., Gray, N. S. 2024

  Abstract

  Targeted covalent inhibition (TCI) and targeted protein degradation (TPD) have proven effective in pharmacologically addressing formerly 'undruggable' targets. Integration of both methodologies has resulted in the development of electrophilic degraders where recruitment of a suitable E3 ubiquitin ligase is achieved through formation of a covalent bond with a cysteine nucleophile. Expanding the scope of electrophilic degraders requires the development of electrophiles with tempered reactivity that enable selective ligase recruitment and reduce cross-reactivity with other cellular nucleophiles. In this study, we report the use of chemical moieties that enable nucleophilic aromatic substitution (SNAr) reactions in the rational design of electrophilic protein degraders. Appending an SNAr covalent warhead to several preexisting small molecule inhibitors transformed them into degraders, obviating the need for a defined E3 ligase recruiter. The SNAr covalent warhead is versatile; it can recruit various E3 ligases, including DDB1 and CUL4 associated factor 11 (DCAF11), DDB1 and CUL4 associated factor 16 (DCAF16), and possibly others. The incorporation of an SNAr covalent warhead into the BRD4 inhibitor led to the discovery of degraders with low picomolar degradation potency. Furthermore, we demonstrate the broad applicability of this approach through rational functional switching from kinase inhibitors into potent degraders.

  View details for DOI 10.1101/2024.09.25.615094

  View details for PubMedID 39386645

  View details for PubMedCentralID PMC11463635