Poster Exhibition Area
Crews Lab, Yale University
12.30 - 12.40 EDT
Targeted Protein Degradation: A Promise from the 21st-century
Induced degradation of disease-causing proteins by heterobifunctional molecules, i.e., PROteolysis TArgeting Chimeras (PROTACs) is emerging as a potential therapeutic modality. In the two decades since the PROTAC concept was proposed, several advancements and new Targeted Protein Degradation (TPD) strategies have been explored to target disease causing proteins, such as transcription factors. In this poster, I discuss the progress and evolution of the TPD field, development of light activatable PROTACs to spatially and temporally control PROTAC activity, and the development of TRAnscription Factor TArgeting Chimeras (TRAFTACs) as a generalizable strategy to induce the degradation of undruggable transcription factors.
12.45 - 12.55 EDT
Modeling CRL4A ligase complex to predict target protein ubiquitination induced by CRBN-recruiting PROTACs
PROteolysis TArgeting Chimeras (PROTACs) are hetero-bifunctional small molecules that can simultaneously recruit target protein and E3 ligase to form a ternary complex (target protein / PROTAC / E3 ligase), leading to target protein ubiquitination and degradation via the Ubiquitin-Proteasome System (UPS). PROTACs have gained increasing attention in recent years due to certain advantages over traditional therapeutic modalities enabling targeting of previously "undruggable" proteins. To better understand the mechanism of PROTAC-induced Target Protein Degradation (TPD), several computational approaches have recently been developed to study and predict ternary complex formation. However, mounting evidence suggests that ubiquitination can also be a rate-limiting step in PROTAC induced TPD. Here, we propose a structure-based computational approach to predict target protein ubiquitination induced by CRBN-based PROTACs by leveraging available CRL4A ligase complex structural information (CRBN/DDB1/CUL4A/Rbx1/NEDD8/E2/Ub). In our method, we generate ternary complex ensembles with Rosetta, model multiple CRL4A ligase complex conformations due to the mobility of DDB1, and predict ubiquitination efficiency by integrating two ensembles and separating the ternary ensemble into productive and unproductive complexes based on the proximity of the ubiquitin to accessible lysines on the target protein. We validate our CRL4A ligase complex models with published ternary complex structures, and employ our modeling workflow to predict ubiquitination efficiencies and sites of a series of Cyclin-dependent kinases (CDKs) after treatment with TL12-186, a pan-kinase PROTAC. Our predictions are consistent with CDK ubiquitination and site-directed mutagenesis of specific CDK lysine residues measured using a NanoBRET ubiquitination assay in HEK293 cells.
Nan Bai1, Kristin M Riching2, Aman Makaju3, Hao Wu1, Timothy M. Acker1, Shu-Ching Ou3, Yaru Zhang4, Xiaomeng Shen1, Daryl Bulloch3, Huan Rui3, Bradford Gibson3, Danette L. Daniels2, Marjeta Urh2, Brooke Rock1, Sara Humphreys1
- Pharmacokinetics and Drug Metabolism, Amgen Research
- Promega Corporation, 5430 E. Cheryl Drive, Madison, WI 53711
- Discovery Attribute Science, Amgen Research
- Oncology, Amgen Research
Bristol Myers Squibb
13.00 - 13.10 EDT
Cereblon Modulators Target ZBTB16 and Its Oncogenic Fusion Partners for Degradation via Distinct Structural Degrons
There is a growing interest in using targeted protein degradation as a therapeutic modality due to its potential to expand the druggable proteome. One avenue to using this modality is via molecular glue based Cereblon E3 Ligase Modulating Drug compounds. Here, we report the identification of the transcription factor ZBTB16 as a Cereblon neosubstrate. We also report two new Cereblon modulators, CC-3060 and CC-647, that promote ZBTB16 degradation. Unexpectedly, CC-3060 and CC-647 target ZBTB16 for degradation by primarily engaging distinct structural degrons on different zinc finger domains. The reciprocal fusion proteins, ZBTB16-RARα and RARα-ZBTB16, which cause a rare acute promyelocytic leukemia, contain these same structural degrons and can be targeted for proteasomal degradation with Cereblon modulator treatment. Thus, a targeted protein degradation approach via Cereblon modulators may represent a novel therapeutic strategy in acute promyelocytic leukemia where ZBTB16/RARA rearrangements are critical disease drivers.
Mary E Matyskiela, Jinyi Zhu, Joshua M Baughman, Thomas Clayton, Michelle Slade, Hon Kit Wong, Kristina Danga, Xinde Zheng, Mark Labow, Laurie LeBrun, Gang Lu, Philip P Chamberlain, and Joel W Thompson
All authors are current or former employees of Bristol Myers Squibb
13.15 - 13.25 EDT
Give your Targeted Protein Degradation research the winning edge
Dimensions L&C applies the latest semantic analysis tools and ontologies on over 120 million scientific publications, as well as millions of patents, grants and clinical trial documents, to create a unique tool for scientists that offers powerful discovery functionality on a new scale. It enables a large variety of possible applications and use cases across targeted protein degradation research, from identification of the E3 ubiquitin ligases for a target protein of interest to discovery of relevant chemical structures connected to E3 ubiquitin ligases/targets of interest.