Back to Search
Start Over
Optimization of a Novel DEL Hit That Binds in the Cbl-b SH2 Domain and Blocks Substrate Binding.
- Source :
-
ACS medicinal chemistry letters [ACS Med Chem Lett] 2024 May 29; Vol. 15 (6), pp. 864-872. Date of Electronic Publication: 2024 May 29 (Print Publication: 2024). - Publication Year :
- 2024
-
Abstract
- We were attracted to the therapeutic potential of inhibiting Casitas B-lineage lymphoma proto-oncogene-b (Cbl-b), a RING E3 ligase that plays a critical role in regulating the activation of T cells. However, given that only protein-protein interactions were involved, it was unclear whether inhibition by a small molecule would be a viable approach. After screening an ∼6 billion member DNA-encoded library (DEL) using activated Cbl-b, we identified compound 1 as a hit for which the cis -isomer ( 2 ) was confirmed by biochemical and surface plasmon resonance (SPR) assays. Our hit optimization effort was greatly accelerated when we obtained a cocrystal structure of 2 with Cbl-b, which demonstrated induced binding at the substrate binding site, namely, the Src homology-2 (SH2) domain. This was quite noteworthy given that there are few reports of small molecule inhibitors that bind to SH2 domains and block protein-protein interactions. Structure- and property-guided optimization led to compound 27 , which demonstrated measurable cell activity, albeit only at high concentrations.<br />Competing Interests: The authors declare no competing financial interest.<br /> (© 2024 American Chemical Society.)
Details
- Language :
- English
- ISSN :
- 1948-5875
- Volume :
- 15
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- ACS medicinal chemistry letters
- Publication Type :
- Academic Journal
- Accession number :
- 38894924
- Full Text :
- https://doi.org/10.1021/acsmedchemlett.4c00068