jm9b01928_si_002.pdf (94.48 kB)
Discovery of CRBN E3 Ligase Modulator CC-92480 for the Treatment of Relapsed and Refractory Multiple Myeloma
journal contribution
posted on 2020-03-19, 01:03 authored by Joshua D. Hansen, Matthew Correa, Mark A. Nagy, Matt Alexander, Veronique Plantevin, Virginia Grant, Brandon Whitefield, Dehua Huang, Timothy Kercher, Roy Harris, Rama Krishna Narla, Jim Leisten, Yang Tang, Mehran Moghaddam, Katalin Ebinger, Joseph Piccotti, Courtney G. Havens, Brian Cathers, James Carmichael, Thomas Daniel, Rupert Vessey, Lawrence G. Hamann, Katerina Leftheris, Derek Mendy, Frans Baculi, Laurie A. LeBrun, Gody Khambatta, Antonia Lopez-GironaMany
patients with multiple myeloma (MM) initially respond to treatment
with modern combination regimens including immunomodulatory agents
(lenalidomide and pomalidomide) and proteasome inhibitors. However,
some patients lack an initial response to therapy (i.e., are refractory),
and although the mean survival of MM patients has more than doubled
in recent years, most patients will eventually relapse. To address
this need, we explored the potential of novel cereblon E3 ligase modulators
(CELMoDs) for the treatment of patients with relapsed or refractory
multiple myeloma (RRMM). We found that optimization beyond potency
of degradation, including degradation efficiency and kinetics, could
provide efficacy in a lenalidomide-resistant setting. Guided by both
phenotypic and protein degradation data, we describe a series of CELMoDs
for the treatment of RRMM, culminating in the discovery of CC-92480,
a novel protein degrader and the first CELMoD to enter clinical development
that was specifically designed for efficient and rapid protein degradation
kinetics.
