Novartis Reports Novel Tissue-Specific E3 Ligase (TRIM58) Ligands for Targeted PROTAC Development

PROTAC based on tissue-specific E3 ligase ligands is expected to have a better safety window. RecentlyNovartis Reports a New Class of Tissue-Specific E3 Ligase (TRIM58) Ligands.TRIM58 is only expressed in erythroblast cells and is suitable for red blood cell-related diseases, such as sickle cell anemia.

Back to the discovery of the molecule. As shown in the screenshot below, a diversity set of 45,000 was initially screened, yielding several hits. Among them, molecule 1 increased the protein melting temperature by 0.5−0.7 °C. Further screening of molecules similar to molecule 1 led to the identification of TRIM-473.Protein melting temperature 2.5 °C. Further validation through other biophysical assays.TRIM-473 is a validated hit, including NMR, SPR, etc., with an SPR KD of 24 μM.

A competitive binding assay was then established.The activity of TRIM-473 in this assay (FP EC50) is 5.3. μM。

The co-crystal structure of this molecule was analyzed. TRIM-473 binds to a relatively shallow pocket, with both basic amines forming polar interactions with acidic residues, while the phenyl substitution exhibits some hydrophobic interactions with surrounding residues.

In general, the electrostatic attraction between a basic amine and an acidic residue is a relatively strong interaction. However, from the SAR perspective, removing one of these two basic amines has little effect on activity (molecule 2, molecule 7, 8), while removing both amines significantly impacts activity (molecule 6). In comparison, removing the benzene ring shows an even more pronounced effect on activity (molecule 9). It can be seen that the contribution of certain interactions to activity must be analyzed on a case-by-case basis and is not so mechanical.Simple。

Possibly due to the poor druggability of the pocket, the article reports that it is difficult to further optimize the activity of this class of molecules. Of course, one advantage of a shallow pocket is that there are more exit vectors available for PROTAC design. As for whether the current level of activity can be successfully applied to PROTAC degradation, further experimental validation is needed.

Novartis Reports E3 Ligase DCAF1 Ligand and Corresponding PROTAC

https://pubs.acs.org/doi/abs/10.1021/acsmedchemlett.3c00259