- Discovery of CRBN E3 Ligase Modulator CC-92480 for the Treatment of Relapsed and Refractory Multiple Myeloma
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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.
- 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
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p. 6648 - 6676
(2020/09/11)
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- Birch Reductive Alkylation of Methyl m-(Hydroxymethyl)benzoate Derivatives and the Behavior of o- and p-(Hydroxymethyl)benzoates under Reductive Alkylation Conditions
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Birch reductive alkylation of methyl m-(hydroxymethyl)benzoate derivatives, using lithium in ammonia-tetrahydrofuran in the presence of tertbutyl alcohol, can be achieved without significant loss of benzylic oxygen substituents. Similar treatment of o- and p-(hydroxymethyl)benzoate derivatives results largely in loss of benzylic oxygen substituents. The results are rationalized by computations describing electron density patterns in the putative radical anion intermediate involved in these reactions.
- Fretz, Samuel J.,Hadad, Christopher M.,Hart, David J.,Vyas, Shubham,Yang, Dexi
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- PHARMACEUTICAL COMPOUNDS
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The invention provides compounds that are useful in the treatment of hepatitis C virus (HCV) infections. The compounds have the formula (1): or a salt, N-oxide, tautomer or stereoisomer thereof, wherein A is CH or N; E is CH or N; R1 is selecte
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Page/Page column 127
(2013/05/22)
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- Fluorous aryldiazirine photoaffinity labeling reagents
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Two fluorous versions of trifluoromethyldiazirine derivatives have been designed and synthesized. The new photoaffinity labeling reagents have reactivity similar to that of their aryltrifluoromethyldiazirine parent when activated in MeOH, while the reacti
- Song, Zhiquan,Zhang, Qisheng
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scheme or table
p. 4882 - 4885
(2010/01/06)
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- Cryptophycin compounds
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The present invention provides cryptophycin compounds of Formula I that are useful in the treatment of neoplasms.
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Page/Page column 150
(2010/02/05)
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- Catalytic Conversions in Water. Part 23: Steric Effects and Increased Substrate Scope in the Palladium-Neocuproine Catalyzed Aerobic Oxidation of Alcohols in Aqueous Solvents
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The steric influence of substituents on the 2-and 9-positions of phenanthroline in the (2,9-R2-1,10-phenanthroline)palladium(II)- catalyzed aerobic oxidation of 2-hexanol was investigated by means of high throughput experimentation. (Neocuproine)Pd-(OAc)2 (R=CH 3) was found to be a highly active catalyst for alcohol oxidation in 1:1 water/DMSO mixtures. The catalyst is unique in that it tolerates water, polar co-solvents and a wide variety of functional groups in the alcohol. Turn-over frequencies of > 1500 h-1 were achieved and a series of alcohols was oxidised with 0.1 to 0.5 mol % of catalyst.
- Ten Brink, Gerd-Jan,Arends, Isabel W. C. E.,Hoogenraad, Marcel,Verspui, Goeran,Sheldon, Roger A.
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p. 1341 - 1352
(2007/10/03)
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- N-benzylpyroglutamyl-L-phenylalanine derivatives as VCAM/VLA-4 antagonists
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A series of N-(N-benzylpyroglutamyl)-4-substituted-L-phenylalanine derivatives was prepared as VLA-4/VCAM antagonists. Analogues substituted by electron deficient benzoylamino groups bearing bulky ortho substituents had low-nM potency in an ELISA assay an
- Chen, Li,Tilley, Jefferson W.,Guthrie, Robert W.,Mennona, Francis,Huang, Tai-Nan,Kaplan, Gerry,Trilles, Richard,Miklowski, Dorota,Huby, Nicolas,Schwinge, Virginia,Wolitzky, Barry,Rowan, Karen
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p. 729 - 733
(2007/10/03)
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- Inhibitors of acyl-coA:cholesterol O-acyltransferase. 2. Identification and structure-activity relationships of a novel series of N-alkyl-N- (heteroaryl-substituted benzyl)-N'-arylureas
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A series of N-alkyl-N-(heteroaryl-substituted benzyl)-N'-arylurea and related derivatives represented by 2 and 3 have been prepared and evaluated for their ability to inhibit acyl-CoA:cholesterol O-acyltransferase in vitro and to lower plasma cholesterol levels in cholesterol-fed rats in vivo. Among these novel compounds, the type 3 series was superior. A pyrazol-3-yl group on the N-benzyl group of this trisubstituted urea (i.e. 3, Ar1 = pyrazol-3- yl) was identified as a heteroaromatic ring providing a good profile of biological activity. As a result of optimization of the combination with the N-alkyl group (R) and N-aryl group (At3), compound 3aq (FR186054) was identified as a new, orally efficacious ACAT inhibitor, which exhibited potent in vitro ACAT inhibitory activity (rabbit intestinal microsomes IC50 = 99 nM) and excellent hypocholesterolemic effects in cholesterol-fed rats, irrespective of administration mode (ED50 = 0.046 mg/kg dosed via the diet, ED50 = 0.44 mg/kg administered by gavage in PEG400 vehicle). Moreover, a toxicological study revealed compound 3aq to be nontoxic to the adrenal glands of dogs when tested at a single dose of 10 mg/kg po.
- Tanaka, Akira,Terasawa, Takeshi,Hagihara, Hiroyuki,Sakuma, Yuri,Ishibe, Noriko,Sawada, Masae,Takasugi, Hisashi,Tanaka, Hirokazu
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p. 2390 - 2410
(2007/10/03)
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