Zixuan Jiang

All Publications

• Discovery of BRD9 Molecular Glue Degraders That Spare Cardiomyocytes. Journal of the American Chemical Society Byun, W. S., Zhuang, Z., Hnatiuk, A. P., Jin, C., Jiang, Z., Baek, K., Chao, E., Donovan, K. A., Fischer, E. S., Mercola, M., Gray, N. S. 2025

  Abstract

  Molecular glue degraders (MGDs) represent a class of drug-like small molecules that induce targeted protein degradation (TPD) by promoting selective protein-protein interactions. MGDs offer a promising therapeutic approach by selectively eliminating disease-associated proteins; however, their rational design and discovery have historically remained a significant challenge. The field remains constrained by a lack of strategies to effectively utilize ubiquitin ligases (E3s) for TPD, thus missing the therapeutic potential offered by tissue-specific E3 expression. In this study, we developed ZZ7, a molecular glue degrader that selectively degrades BRD9, a critical component of the SWI/SNF chromatin remodeling complex, specifically in synovial sarcoma cells, while sparing cardiomyocytes. The discovery of ZZ7 was driven by a "chemocentric" approach, incorporating a cysteine-reactive, reversible covalent warhead into a BRD9 inhibitor to transform its function from inhibition to degradation. ZZ7 covalently engages DCAF16 at Cys178, an E3 ligase that is highly expressed in synovial sarcoma cells but relatively underexpressed in human iPSC-derived cardiomyocytes, leveraging a cysteine residue that has not been previously exploited. These findings pave the way for new strategies in tissue- and disease-specific precision therapies, particularly for malignancies characterized by an elevated level of DCAF16 expression.

  View details for DOI 10.1021/jacs.5c09857

  View details for PubMedID 40960846

• Rational Design of CDK12/13 and BRD4 Molecular Glue Degraders. Angewandte Chemie (International ed. in English) Gray, N. S., Zhuang, Z., Byun, W. S., Kozicka, Z., Donovan, K., Dwyer, B., Thornhill, A., Jones, H., Jiang, Z., Zhu, X., Fischer, E., Thomä, N. 2025: e202508427

  Abstract

  Targeted protein degradation (TPD) is an emerging therapeutic approach for the selective elimination of disease-related proteins. While molecular glue degraders exhibit drug-like properties, their discovery has traditionally been serendipitous and often requires post-hoc rationalization. In this study, we demonstrate the rational, mechanism-guided design of molecular glue degraders using gluing moieties. Building on established principles, by appending a chemical gluing moiety to several small molecule inhibitors, we successfully transformed them into degraders, obviating the need for a specific E3 ubiquitin ligase recruiter. Specifically, we found that incorporating a hydrophobic aromatic ring or a double bond into a cyclin-dependent kinase 12 and 13 (CDK12/13) dual inhibitor enabled the recruitment of DNA damage-binding protein 1 (DDB1), thereby transforming a high-molecular-weight bivalent CDK12 degrader into a potent monovalent CDK12/13 molecular glue degrader. We also showcase that attaching a cysteine-reactive warhead to a bromodomain-containing protein 4 (BRD4) inhibitor converts it into a degrader by recruiting the DDB1 and CUL4 associated factor 16 (DCAF16) E3 ligase.

  View details for DOI 10.1002/anie.202508427

  View details for PubMedID 40626960

• Development of Potent and Selective CK1α Molecular Glue Degraders. Journal of medicinal chemistry Geng, Q., Jiang, Z., Byun, W. S., Donovan, K. A., Zhuang, Z., Jiang, F., Jones, H. M., Razumkov, H., Tang, M. T., Sarott, R. C., Fischer, E. S., Corsello, S. M., Hinshaw, S. M., Gray, N. S. 2025

  Abstract

  Molecular glue degraders (MGDs) are small molecules that facilitate proximity between a target protein and an E3 ubiquitin ligase, thereby inducing target protein degradation. Glutarimide-containing compounds are MGDs that bind cereblon (CRBN) and recruit neosubstrates. Through explorative synthesis of a glutarimide-based library, we discovered a series of molecules that induce casein kinase 1 alpha (CK1α) degradation. By scaffold hopping and rational modification of the chemical scaffold, we identified an imidazo[1,2-a]pyrimidine compound that induces potent and selective CK1α degradation. A structure-activity relationship study of the lead compound, QXG-6442, identified the chemical features that contribute to degradation potency and selectivity compared to other frequently observed neosubstrates. The glutarimide library screening and structure-activity relationship medicinal chemistry approach we employed is generally useful for developing new molecular glue degraders toward new targets of interest.

  View details for DOI 10.1021/acs.jmedchem.4c02415

  View details for PubMedID 39873536

• Discovery of CRBN-Dependent WEE1 Molecular Glue Degraders from a Multicomponent Combinatorial Library. Journal of the American Chemical Society Razumkov, H., Jiang, Z., Baek, K., You, I., Geng, Q., Donovan, K. A., Tang, M. T., Metivier, R. J., Mageed, N., Seo, P., Li, Z., Byun, W. S., Hinshaw, S. M., Sarott, R. C., Fischer, E. S., Gray, N. S. 2024

  Abstract

  Small molecules promoting protein-protein interactions produce a range of therapeutic outcomes. Molecular glue degraders exemplify this concept due to their compact drug-like structures and ability to engage targets without reliance on existing cognate ligands. While cereblon molecular glue degraders containing glutarimide scaffolds have been approved for treatment of multiple myeloma and acute myeloid leukemia, the design of new therapeutically relevant monovalent degraders remains challenging. We report here an approach to glutarimide-containing molecular glue synthesis using multicomponent reactions as a central modular core-forming step. Screening the resulting library identified HRZ-1 derivatives that target casein kinase 1 α (CK1α) and Wee-like protein kinase (WEE1). Further medicinal chemistry efforts led to identification of selective monovalent WEE1 degraders that provide a potential starting point for the eventual development of a selective chemical degrader probe. The structure of the hit WEE1 degrader complex with CRBN-DDB1 and WEE1 provides a model of the protein-protein interface and ideas to rationalize the observed kinase selectivity. Our findings suggest that modular synthetic routes combined with in-depth structural characterization give access to selective molecular glue degraders and expansion of the CRBN-degradable proteome.

  View details for DOI 10.1021/jacs.4c06127

  View details for PubMedID 39499896

• Activating p53Y220C with a Mutant-Specific Small Molecule. bioRxiv : the preprint server for biology Zhu, X., Byun, W. S., Pieńkowska, 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

• 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

• Discovery of Potent Degraders of the Dengue Virus Envelope Protein. Advanced science (Weinheim, Baden-Wurttemberg, Germany) Li, Z., Liu, H. Y., He, Z., Chakravarty, A., Golden, R. P., Jiang, Z., You, I., Yue, H., Donovan, K. A., Du, G., Che, J., Tse, J., Che, I., Lu, W., Fischer, E. S., Zhang, T., Gray, N. S., Yang, P. L. 2024: e2405829

  Abstract

  Targeted protein degradation has been widely adopted as a new approach to eliminate both established and previously recalcitrant therapeutic targets. Here, it is reported that the development of small molecule degraders of the envelope (E) protein of dengue virus. Two classes of bivalent E-degraders are developed by linking two previously reported E-binding small molecules, GNF-2, and CVM-2-12-2, to a glutarimide-based recruiter of the CRL4CRBN ligase to effect proteosome-mediated degradation of the E protein. ZXH-2-107 (based on GNF-2) is an E-degrader with ABL inhibitory activity while ZXH-8-004 (based on CVM-2-12-2) is a selective and potent E-degrader. These two compounds provide proof of concept that difficult-to-drug targets such as a viral envelope protein can be effectively eliminated using a bivalent degrader and provide starting points for the future development of a new class of direct-acting antiviral drugs.

  View details for DOI 10.1002/advs.202405829

  View details for PubMedID 39145423

• Discovery of bivalent small molecule degraders of cyclin-dependent kinase 7 (CDK7). European journal of medicinal chemistry Ji, W., Du, G., Jiang, J., Lu, W., Mills, C. E., Yuan, L., Jiang, F., He, Z., Bradshaw, G. A., Chung, M., Jiang, Z., Byun, W. S., Hinshaw, S. M., Zhang, T., Gray, N. S. 2024; 276: 116613

  Abstract

  Cyclin-dependent kinase 7, along with cyclin H and MAT1, forms the CDK-activating complex (CAK), which directs cell cycle progression via T-loop phosphorylation of cell cycle CDKs. Pharmacological inhibition of CDK7 leads to selective anti-cancer effects in cellular and in vivo models, motivating several ongoing clinical investigations of this target. Current CDK7 inhibitors are either reversible or covalent inhibitors of its catalytic activity. We hypothesized that small molecule targeted protein degradation (TPD) might result in differentiated pharmacology due to the loss of scaffolding functions. Here, we report the design and characterization of a potent CDK7 degrader that is comprised of an ATP-competitive CDK7 binder linked to a CRL2VHL recruiter. JWZ-5-13 effectively degrades CDK7 in multiple cancer cells and leads to a potent inhibition of cell proliferation. Additionally, compound JWZ-5-13 displayed bioavailability in a pharmacokinetic study conducted in mice. Therefore, JWZ-5-13 is a useful chemical probe to investigate the pharmacological consequences of CDK7 degradation.

  View details for DOI 10.1016/j.ejmech.2024.116613

  View details for PubMedID 39004018

• Discovery of Potent Degraders of the Dengue Virus Envelope Protein. bioRxiv : the preprint server for biology Li, Z., Liu, H. Y., He, Z., Chakravarty, A., Golden, R. P., Jiang, Z., You, I., Yue, H., Donovan, K. A., Du, G., Che, J., Tse, J., Che, I., Lu, W., Fischer, E. S., Zhang, T., Gray, N. S., Yang, P. L. 2024

  Abstract

  Targeted protein degradation has been widely adopted as a new approach to eliminate both established and previously recalcitrant therapeutic targets. Here we report the development of small molecule degraders of the envelope (E) protein of dengue virus. We developed two classes of bivalent E-degraders, linking two previously reported E-binding small molecules, GNF-2 and CVM-2-12-2, to a glutarimide-based recruiter of the CRL4CRBN ligase to effect proteosome-mediated degradation of the E protein. ZXH-2-107 (based on GNF-2) is an E degrader with ABL inhibition while ZXH-8-004 (based on CVM-2-12-2) is a selective and potent E-degrader. These two compounds provide proof-of-concept that difficult-to-drug targets such as a viral envelope protein can be effectively eliminated using a bivalent degrader and provide starting points for the future development of a new class antiviral drugs.

  View details for DOI 10.1101/2024.06.01.596987

  View details for PubMedID 38854003

  View details for PubMedCentralID PMC11160776