903890-66-4Relevant articles and documents
Discovery of CRBN E3 Ligase Modulator CC-92480 for the Treatment of Relapsed and Refractory Multiple Myeloma
Hansen, Joshua D.,Correa, Matthew,Nagy, Mark A.,Alexander, Matt,Plantevin, Veronique,Grant, Virginia,Whitefield, Brandon,Huang, Dehua,Kercher, Timothy,Harris, Roy,Narla, Rama Krishna,Leisten, Jim,Tang, Yang,Moghaddam, Mehran,Ebinger, Katalin,Piccotti, Joseph,Havens, Courtney G.,Cathers, Brian,Carmichael, James,Daniel, Thomas,Vessey, Rupert,Hamann, Lawrence G.,Leftheris, Katerina,Mendy, Derek,Baculi, Frans,Lebrun, Laurie A.,Khambatta, Gody,Lopez-Girona, Antonia
, p. 6648 - 6676 (2020/09/11)
Many 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.
Stereospecific Alkylation of the Schiff Base Ester of Alanine with 2-Substituted-(E)- and -(Z)-vinyl Bromides. An Efficient Synthesis of 2-Methyl-(E)-3,4-didehydroglutamic Acid, a Potent Substrate-Induced Irreversible Inhibitor of L-Glutamate-1-decarboxylase.
Bey, Philippe,Vevert, Jean Paul
, p. 3249 - 3253 (2007/10/02)
The nucleophilic vinylic substitution by the enolate of methyl N-benzylidenealanate (1) of (E)- and (Z)-vinylbromides 4 and 5 has been examined as an approach to the synthesis of the E and Z isomers of 2-methyl-3,4-didehydroglutamic acid.Under aprotic conditions, the nucleophilic displacement has been found to proceed stereospecifically with retention of configuration of the double bond to afford in good yield the corresponding (E)- and (Z)-substituted products.The configuration of the substitution products has been assigned from the analysis of their 1H NMR spectra on the basis of the value of the coupling constant of the vicinal vinyl ic protons.Subsequent removal of the protecting groups from the substitution products 6 in the E series gives the corresponding 2-methyl-(E)-3,4-didehydroglutamic acid derivatives 2 in good yield.The Z isomers 3 prove to be very unstable and have not been isolated.
