2. Academic Validation
  3. Synthetic and structure-activity studies of SP2577 and TCP towards LSD1 targeting PROTACs

Synthetic and structure-activity studies of SP2577 and TCP towards LSD1 targeting PROTACs

  • RSC Med Chem. 2025 Aug 5;16(10):4952-4959. doi: 10.1039/d5md00420a.
Megan E Coulson 1 2,  James K S Norris 1,  Sean A Smith 1,  Joshua P Smalley 1,  John W R Schwabe 3,  Shaun M Cowley 2,  James T Hodgkinson 1
Affiliations

Affiliations

  • 1 Leicester Institute of Structural and Chemical Biology and School of Chemistry, University of Leicester University Road Leicester LE1 7RH UK [email protected].
  • 2 Department of Molecular and Cell Biology, University of Leicester Leicester LE1 9HN UK [email protected].
  • 3 Leicester Institute of Structural and Chemical Biology and Department of Molecular and Cell Biology, University of Leicester Leicester LE1 9HN UK [email protected].
PMID: 40771285 DOI: 10.1039/d5md00420a
Abstract

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 in vitro in the HDAC1-CoREST-LSD1 complex (43 nM and 63 nM respectively). Our findings provide important SAR data towards LSD1 PROTACs.

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