Principles of paralog-specific targeted protein degradation engaging the C-degron E3 KLHDC2

Daniel C. Scott, Suresh Dharuman, Elizabeth Griffith, Sergio C. Chai, Jarrid Ronnebaum, Moeko T. King, Rajendra Tangallapally, Chan Lee, Clifford T. Gee, Lei Yang, Yong Li, Victoria C. Loudon, Ha Won Lee, Jason Ochoada, Darcie J. Miller, Thilina Jayasinghe, Joao A. Paulo, Stephen J. Elledge, J. Wade Harper, Taosheng Chen, Richard E. Lee () and Brenda A. Schulman ()
Additional contact information
Daniel C. Scott: St. Jude Children’s Research Hospital
Suresh Dharuman: St. Jude Children’s Research Hospital
Elizabeth Griffith: St. Jude Children’s Research Hospital
Sergio C. Chai: St. Jude Children’s Research Hospital
Jarrid Ronnebaum: St. Jude Children’s Research Hospital
Moeko T. King: St. Jude Children’s Research Hospital
Rajendra Tangallapally: St. Jude Children’s Research Hospital
Chan Lee: Harvard Medical School
Clifford T. Gee: St. Jude Children’s Research Hospital
Lei Yang: St. Jude Children’s Research Hospital
Yong Li: St. Jude Children’s Research Hospital
Victoria C. Loudon: St. Jude Children’s Research Hospital
Ha Won Lee: St. Jude Children’s Research Hospital
Jason Ochoada: St. Jude Children’s Research Hospital
Darcie J. Miller: St. Jude Children’s Research Hospital
Thilina Jayasinghe: St. Jude Children’s Research Hospital
Joao A. Paulo: Harvard Medical School
Stephen J. Elledge: Department of Genetics, Harvard Medical School
J. Wade Harper: Harvard Medical School
Taosheng Chen: St. Jude Children’s Research Hospital
Richard E. Lee: St. Jude Children’s Research Hospital
Brenda A. Schulman: St. Jude Children’s Research Hospital

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: Abstract PROTAC® (proteolysis-targeting chimera) molecules induce proximity between an E3 ligase and protein-of-interest (POI) to target the POI for ubiquitin-mediated degradation. Cooperative E3-PROTAC-POI complexes have potential to achieve neo-substrate selectivity beyond that established by POI binding to the ligand alone. Here, we extend the collection of ubiquitin ligases employable for cooperative ternary complex formation to include the C-degron E3 KLHDC2. Ligands were identified that engage the C-degron binding site in KLHDC2, subjected to structure-based improvement, and linked to JQ1 for BET-family neo-substrate recruitment. Consideration of the exit vector emanating from the ligand engaged in KLHDC2’s U-shaped degron-binding pocket enabled generation of SJ46421, which drives formation of a remarkably cooperative, paralog-selective ternary complex with BRD3BD2. Meanwhile, screening pro-drug variants enabled surmounting cell permeability limitations imposed by acidic moieties resembling the KLHDC2-binding C-degron. Selectivity for BRD3 compared to other BET-family members is further manifested in ubiquitylation in vitro, and prodrug version SJ46420-mediated degradation in cells. Selectivity is also achieved for the ubiquitin ligase, overcoming E3 auto-inhibition to engage KLHDC2, but not the related KLHDC1, KLHDC3, or KLHDC10 E3s. In sum, our study establishes neo-substrate-specific targeted protein degradation via KLHDC2, and provides a framework for developing selective PROTAC protein degraders employing C-degron E3 ligases.

Date: 2024
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DOI: 10.1038/s41467-024-52966-3

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