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

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.