Qixiang Geng

All Publications

• 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

• Targeting the Dark Lipid Kinase PIP4K2C with aPotent and Selective Binder and Degrader. Angewandte Chemie (International ed. in English) Teng, M., Jiang, J., Wang, E. S., Geng, Q., Toenjes, S. T., Donovan, K. A., Mageed, N., Yue, H., Nowak, R. P., Wang, J., Manz, T. D., Fischer, E. S., Cantley, L. C., Gray, N. S. 2023: e202302364

  Abstract

  Phosphatidylinositol 5-phosphate 4-kinase, type II, gamma (PIP4K2C) remains a poorly understood lipid kinase with minimal enzymatic activity but potential scaffolding roles in immune modulation and autophagy-dependent catabolism. Achieving potent and selective agents for PIP4K2C while sparing other lipid and non-lipid kinases has been challenging. Here, we report the discovery of the highly potent PIP4K2C binder TMX-4102, which shows exclusive binding selectivity for PIP4K2C. Furthermore, we elaborated this molecule into TMX-4153, a bivalent degrader capable of rapidly and selectively degrading endogenous PIP4K2C. Collectively, our work demonstrates that PIP4K2C is a tractable and a degradable target, and that TMX-4102 and TMX-4153 are useful leads to further interrogate the biological roles and therapeutic potential of PIP4K2C.

  View details for DOI 10.1002/anie.202302364

  View details for PubMedID 36898968

• Development of a Covalent Inhibitor of c-Jun N-Terminal Protein Kinase (JNK) 2/3 with Selectivity over JNK1. Journal of medicinal chemistry Lu, W., Liu, Y., Gao, Y., Geng, Q., Gurbani, D., Li, L., Ficarro, S. B., Meyer, C. J., Sinha, D., You, I., Tse, J., He, Z., Ji, W., Che, J., Kim, A. Y., Yu, T., Wen, K., Anderson, K. C., Marto, J. A., Westover, K. D., Zhang, T., Gray, N. S. 2023

  Abstract

  The c-Jun N-terminal kinases (JNKs) are members of the mitogen-activated protein kinase (MAPK) family, which includes JNK1-JNK3. Interestingly, JNK1 and JNK2 show opposing functions, with JNK2 activity favoring cell survival and JNK1 stimulating apoptosis. Isoform-selective small molecule inhibitors of JNK1 or JNK2 would be useful as pharmacological probes but have been difficult to develop due to the similarity of their ATP binding pockets. Here, we describe the discovery of a covalent inhibitor YL5084, the first such inhibitor that displays selectivity for JNK2 over JNK1. We demonstrated that YL5084 forms a covalent bond with Cys116 of JNK2, exhibits a 20-fold higher Kinact/KI compared to that of JNK1, and engages JNK2 in cells. However, YL5084 exhibited JNK2-independent antiproliferative effects in multiple myeloma cells, suggesting the existence of additional targets relevant in this context. Thus, although not fully optimized, YL5084 represents a useful chemical starting point for the future development of JNK2-selective chemical probes.

  View details for DOI 10.1021/acs.jmedchem.2c01834

  View details for PubMedID 36826833