Hunter P. Shunatona, Natalie Holmberg Douglas, Jayce Rhodes, William J. W. Thomas, Diogo Silva, Jim Gamez, Matthew Groza, Andy Christoforou, J. Zhu, S.A. Johnson, Dharmpal S. Dodd, Dehua Huang, Jennifer K. Griffin, Giulianna A. Miseo, Brandon Whitefield, Dahlia R. Weiss, James Rader, Elif Kuzu, Jim Leisten, Joselyn Del Rosario, Lihong Shi, Mary E. Matyskiela, Philip P. Chamberlain, Peter Belmont, Matt Alexander, Christoph W. Zapf, Lynda Groocock, Deborah S. Mortensen
) 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.