Summary for 9QE5
| Entry DOI | 10.2210/pdb9qe5/pdb |
| Related | 9QE4 |
| Descriptor | Elongin-B, Elongin-C, von Hippel-Lindau disease tumor suppressor, ... (5 entities in total) |
| Functional Keywords | protac, degrader, complex, e3 ligase, vhl, vcb, ligase |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 12 |
| Total formula weight | 198139.53 |
| Authors | Braun, M.B.,Dierlamm, N.,Hartmann, M.D. (deposition date: 2025-03-07, release date: 2025-04-23, Last modification date: 2025-11-19) |
| Primary citation | Wittenburg, S.,Zuleeg, M.R.,Peter, K.,Lemnitzer, P.,Voget, R.,Bricelj, A.,Gobec, M.,Dierlamm, N.,Braun, M.B.,Geiger, T.M.,Heim, C.,Stakemeier, A.,Wagner, K.G.,Nowak, R.P.,Hartmann, M.D.,Sosic, I.,Gutschow, M.,Kronke, J.,Steinebach, C. Enhancing Solubility in VHL-Based PROTACs: Optimized USP7 Degraders for Improved Developability. J.Med.Chem., 68:15711-15737, 2025 Cited by PubMed Abstract: Limited aqueous solubility, high total polar surface area (TPSA), and high hydrogen-bond donor (HBD) counts have hampered the clinical development of VHL-based proteolysis-targeting chimeras (PROTACs). This study explores strategies to enhance the physicochemical properties of VHL-recruiting USP7 degraders. By adjusting lipophilicity, HBD count, and TPSA, we created degraders with improved solubility while maintaining their USP7 degradation capability. Structural modifications at the VHL ligand included a constrained six-membered ring in the peptidic scaffold and the addition of solubilizing groups. These changes enhanced aqueous solubility without compromising degradation performance. A key example is PROTAC , modified with a dibasic piperazine, which exhibits a 170-fold increase in solubility over its predecessor while retaining strong target selectivity. The findings demonstrate that rational scaffold design can yield solubility-enhanced VHL-based PROTACs with broad potential for drug development. This methodology may also be applicable to other E3 ligases, supporting the development of degraders suitable for use. PubMed: 40673806DOI: 10.1021/acs.jmedchem.5c00718 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.5 Å) |
Structure validation
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