Synthetic and structure–activity studies of SP2577 and TCP towards LSD1 targeting PROTACs
Lysine-specific histone demethylase 1A (LSD1) is involved in epigenetic regulation and is a viable drug target with a number of LSD1 inhibitors in clinical trials. We report synthetic and structure-activity studies of two LSD1 inhibitors, TCP and SP2577, in clinical trials towards PROTAC development. 16 Heterobifunctional molecules were synthesised based on TCP and SP2577. No LSD1 degraders were identified in HCT116 cells, however two TCP analogues functionalised from the phenyl ring with an aklyl and PEG linker in combination with a VHL ligand demonstrated potent LSD1 inhibition <i>in vitro</i> in the HDAC1-CoREST-LSD1 complex (43 nM and 63 nM respectively). Our findings provide important SAR data towards LSD1 PROTACs.
Authors
- Megan E. Coulson (ORCID: https://orcid.org/0000-0003-1058-4241)
- Shaun M. Cowley (ORCID: https://orcid.org/0000-0002-2510-1305)
- S. A. Smith (ORCID: https://orcid.org/0000-0002-0901-3444)
- James T. Hodgkinson (ORCID: https://orcid.org/0000-0001-9978-7322)
- Joshua P. Smalley (ORCID: https://orcid.org/0000-0003-4973-784X)
- John W. R. Schwabe (ORCID: https://orcid.org/0000-0003-2865-4383)
- James K. S. Norris (ORCID: https://orcid.org/0000-0002-1224-2010)
Institutions
- University of Leicester (GB)
Publication Details
- Journal
- RSC Medicinal Chemistry
- Published
- 2025-01-01
- DOI
- https://doi.org/10.1039/d5md00420a
- Citations
- 2
- Primary Topic
- Protein Degradation and Inhibitors
- Type
- article
- Field-Weighted Citation Impact
- 1.61
Funders
- Ministerio de Economía y Competitividad
- Medical Research Council
- Engineering and Physical Sciences Research Council
- Biotechnology and Biological Sciences Research Council