2. Academic Validation
  3. Discovery of Potent and Selective BCL6 Ligand-Directed Degrader (LDD), BCL6-760

Discovery of Potent and Selective BCL6 Ligand-Directed Degrader (LDD), BCL6-760

  • J Med Chem. 2025 Oct 23;68(20):21502-21519. doi: 10.1021/acs.jmedchem.5c01645.
Hunter P Shunatona 1,  Natalie Holmberg Douglas 1,  Jayce Rhodes 1,  William Thomas 1,  Diogo Da Silva 1,  Jim Gamez 1,  Matt Groza 1,  Andy Christoforou 1,  Jinyi Zhu 1,  Scott Johnson 1,  Dharmpal Dodd 1,  Dehua Huang 1,  Jennifer Griffin 1,  Giulianna Miseo 1,  Brandon Whitefield 1,  Dahlia Weiss 1,  James Rader 1,  Elif Kuzu 1,  Jim Leisten 1,  Joselyn Del Rosario 1,  Lihong Shi 1,  Mary Matyskiela 1,  Philip P Chamberlain 1,  Peter Belmont 1,  Matt Alexander 1,  Christoph W Zapf 1,  Lynda Groocock 1,  Deborah S Mortensen 1
Affiliations

Affiliation

  • 1 Bristol Myers Squibb, 10300 Campus Point Dr. Suite 100, San Diego, California 92121, United States.
PMID: 41055242 DOI: 10.1021/acs.jmedchem.5c01645
Abstract

The discovery of a potent and selective BCL6 ligand-directed degrader (LDD), BCL6-760 (45) is described. Through structure-activity relationships, the most potent heterobifunctional degraders of BCL6 were found to be those containing short aminopiperidine linkers in combination with an indazole-based Cereblon (CRBN)-binding moiety (CBM). In vitro ADME profiling of potent molecules identified BCL6-760 as an ideal molecule for use in in vivo experiments due to its good passive permeability, solubility, and microsomal stability. Mechanistic studies confirmed that BCL6 degradation is CRBN mediated, and proteomic assessment indicates a clean and selective degradation profile. BCL6-760 exhibited good oral mouse PK and was capable of penetrant and sustained PD effects. At 60 mg/kg BID dosing, BCL6-760 achieves >90% BCL6 reduction and leads to an overall 64% tumor volume reduction in an OCI-LY-1 mouse xenograft efficacy model.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-178777
    BCL-6 PROTAC Degrader