2. Academic Validation
  3. Discovery and Characterization of Novel BLIMP-1 Heterobifunctional Ligand-Directed Degraders

Discovery and Characterization of Novel BLIMP-1 Heterobifunctional Ligand-Directed Degraders

  • J Med Chem. 2025 Dec 11;68(23):25385-25402. doi: 10.1021/acs.jmedchem.5c02363.
Bryan J Simmons 1,  Lynda Groocock 1,  Jesus Moreno 1,  David S Peters 1,  Meredith E Hughes 1,  Vijay Veeravalli 1,  Jennifer M Crawford 1,  Matthew Chalkley 2,  Mark Griffith 1,  Melissa Plooster 1,  Bo Hu 1,  Jim Gamez 1,  Jim Leisten 1,  Michael J Barnes 3,  Jason Chinn 3,  Gauri Deb 1,  Hardik Modi 1,  Madhu Katepalli 3,  Dahlia Weiss 2,  Walter Won 1,  Zhenghang Sun 1,  Shan Yu 1,  Cameron Reid 1,  Andrew F Donnell 4,  Ling Li 4,  Edmond R Watson 1,  Sophie Perrin-Ninkovic 1,  Lihong Shi 1,  Rama Krishna Narla 1,  Christoph W Zapf 1,  Neil Bence 1,  Antonia Lopez-Girona 1,  Jennifer R Riggs 1
Affiliations

Affiliations

  • 1 Bristol Myers Squibb, 10300 Campus Point Dr. Suite 100, San Diego, California 92121, United States.
  • 2 Bristol Myers Squibb, 700 Bay Road, Redwood City, California 94063, United States.
  • 3 Bristol Myers Squibb, 400 Dexter Ave N, Seattle, Washington 98109, United States.
  • 4 Bristol Myers Squibb, 3551 Lawrenceville Rd, Lawrence Township, New Jersey 08648, United States.
PMID: 41284831 DOI: 10.1021/acs.jmedchem.5c02363
Abstract

B-lymphocyte-induced maturation protein 1 (BLIMP-1/PRDM1) is a master transcriptional repressor essential for terminal differentiation of activated B-cells into bone-marrow resident plasma cells. Multiple myeloma (MM) is a plasma cell malignancy wherein the BLIMP-1 regulon remains critical to support basal cell functions, such as an elevated metabolic state and immunoglobulin production that underlie disease manifestation and tumor cell proliferation. It is predicted that perturbation of BLIMP-1 will significantly impact tumor cell homeostasis and ultimately reduce MM cell survival. Herein, we describe the discovery and optimization of the first orally bioavailable BLIMP-1 heterobifunctional ligand-directed degrader (LDD) and demonstration of the expected antitumor response and immunomodulatory biology following BLIMP-1 degradation using preclinical in vivo MM models.

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