A Roadmap for PROTAC Development

Category:2018, News
ByUoD Web Team
On12 Dec 2018

Our SAR story disclosing dual Brd7/9 PROTAC degrader VZ185 is published in J. Med. Chem.

Congratulations to Vittoria, Scott, Chiara and Andrea, and all our collaborators for their contributions to this work!

Related Links

Promega Connections blog: “A Roadmap for PROTAC Development”

ToC Graphic for SAR story disclosing dual Brd7/9 PROTAC degrader VZ185 is published in J. Med. Chem

Figure 1. Chemical structures of parent (1a, 1b, 2–4) and modified (1c, 2a–4a) BRD7/9 and E3 ligase ligands. Functional groups selected for conjugation are shown in blue on parent ligands and in red on modified ligands.

Scheme 1. Synthesis of the BRD7/9 Ligand 1c

Scheme 2. Synthesis of the First Generation of Degraders

Figure 2. Screening of first generation of degraders.

Figure 3. Structures of compounds 7 and 21.

Figure 4. Ternary complex formation and analysis of binding mode for compound 5.

Scheme 3. Synthesis of Compound 23

Scheme 4. Synthesis of Compounds 26–31

Figure 5. Compound 26 induces rapid and profound depletion of BRD9 in cells

Figure 6. Improved ternary complex formation by series-2 degraders.

Scheme 5. General Synthetic Routes for Third-Generation Compounds

Figure 7. Screening of third generation of degraders

Figure 8. VZ185 induces strong and rapid degradation in a time- and dose-dependent manner.

Figure 9. Quantitative live-cell kinetics of VZ185 induced degradation of BRD7 and BRD9

Figure 9. Quantitative live-cell kinetics of VZ185 induced degradation of BRD7 and BRD9

Figure 11. Effect of BRD7/9 degradation on viability of BRD9-sensitive cancer cell lines.

Figure 12. Impact of VZ185 on the cellular proteome after treatment of RI-1 cells with 100 nM compound for 4 h before harvesting.