Tuesday, July 27, 2021

Exploring Ligand-Directed N-Acyl-N-alkylsulfonamide-Based Acylation Chemistry for Potential Targeted Degrader Development

Mingxing Teng, Jie Jiang, Scott B. Ficarro, Hyuk-Soo Seo, Jae Hyun Bae, Katherine A. Donovan, Eric S. Fischer, Tinghu Zhang, Sirano Dhe-Paganon, Jarrod A. Marto, and Nathanael S. Gray

ACS Medicinal Chemistry Letters 2021

DOI: 10.1021/acsmedchemlett.1c00285

Ligand-directed bioconjugation strategies have been used for selective protein labeling in live cells or tissue samples in applications such as live-cell imaging. Here we hypothesized that a similar strategy could be used for targeted protein degradation. To test this possibility, we developed a series of CDK2-targeting N-acyl-N-alkylsulfonamide (NASA)-containing acylation probes. The probes featured three components: a CDK2 homing ligand, a CRL4CRBN E3 ligase recruiting ligand, and a NASA functionality. We determined that upon target binding, NASA-mediated reaction resulted in selective functionalization of Lys89 on purified or native CDK2. However, we were unable to observe CDK2 degradation, which is in contrast to the efficient degradation achieved by the use of a structurally similar reversible bivalent degrader. Our analysis suggests that the lack of degradation is due to the failure to form a productive CDK2:CRBN complex. Therefore, although this work demonstrates that NASA chemistry can be used for protein labeling, whether this strategy could enable efficient protein degradation remains an open question.

Oncogenic KRAS G12C: Kinetic and Redox Characterization of Covalent Inhibition

Minh V. Huynh, Derek Parsonage, Tom E. Forshaw, Venkat R. Chirasani, G. Aaron Hobbs, Hanzhi Wu, Jingyun Lee, Cristina M. Furdui, Leslie B. P...