- Discovery of AG-120 (Ivosidenib): A First-in-Class Mutant IDH1 Inhibitor for the Treatment of IDH1 Mutant Cancers
-
Somatic point mutations at a key arginine residue (R132) within the active site of the metabolic enzyme isocitrate dehydrogenase 1 (IDH1) confer a novel gain of function in cancer cells, resulting in the production of d-2-hydroxyglutarate (2-HG), an oncometabolite. Elevated 2-HG levels are implicated in epigenetic alterations and impaired cellular differentiation. IDH1 mutations have been described in an array of hematologic malignancies and solid tumors. Here, we report the discovery of AG-120 (ivosidenib), an inhibitor of the IDH1 mutant enzyme that exhibits profound 2-HG lowering in tumor models and the ability to effect differentiation of primary patient AML samples ex vivo. Preliminary data from phase 1 clinical trials enrolling patients with cancers harboring an IDH1 mutation indicate that AG-120 has an acceptable safety profile and clinical activity.
- Popovici-Muller, Janeta,Lemieux, René M.,Artin, Erin,Saunders, Jeffrey O.,Salituro, Francesco G.,Travins, Jeremy,Cianchetta, Giovanni,Cai, Zhenwei,Zhou, Ding,Cui, Dawei,Chen, Ping,Straley, Kimberly,Tobin, Erica,Wang, Fang,David, Muriel D.,Penard-Lacronique, Virginie,Quivoron, Cyril,Saada, Véronique,De Botton, Stéphane,Gross, Stefan,Dang, Lenny,Yang, Hua,Utley, Luke,Chen, Yue,Kim, Hyeryun,Jin, Shengfang,Gu, Zhiwei,Yao, Gui,Luo, Zhiyong,Lv, Xiaobing,Fang, Cheng,Yan, Liping,Olaharski, Andrew,Silverman, Lee,Biller, Scott,Su, Shin-San M.,Yen, Katharine
-
supporting information
p. 300 - 305
(2018/04/20)
-
- THERAPEUTICALLY ACTIVE COMPOUNDS AND THEIR METHODS OF USE
-
Provided are methods of treating a cancer characterized by the presence of a mutant allele of IDH1/2 comprising administering to a subject in need thereof a compound described here.
- -
-
Page/Page column
(2015/03/31)
-
- THERAPEUTICALLY ACTIVE COMPOUNDS AND THEIR METHODS OF USE
-
Provided are methods of treating a cancer characterized by the presence of a mutant allele of IDH1/2 comprising administering to a subject in need thereof a compound described here.
- -
-
Page/Page column 76
(2013/07/31)
-
- Tandem radical decarboxylation-oxidation of amino acids: A mild and efficient method for the generation of N-acyliminium ions and their nucleophilic trapping
-
A convenient methodology for the synthesis of 2-substituted pyrrolidines from α-amino acids is described. A number of cyclic and acyclic α-amino acid derivatives have been prepared in order to test the scope and diastereoselectivity of this method. These substrates were treated with iodosylbenzene or (diacetoxyiodo)benzene (DIB) and iodine in order to generate the corresponding carboxyl radical, which evolves by loss of carbon dioxide to produce a carbon radical which in turn undergoes oxidation to an N-acyliminium ion. This postulated intermediate could be trapped inter- or intramolecularly by oxygen, nitrogen and carbon nucleophiles. In the case of carbon nucleophiles, a Lewis acid is required for the concomitant carbon-carbon bond formation. High yields and modest diastereoselectivities were obtained. The present methodology was applied to the synthesis of ω-amino aldehydes or hemiaminals 8-14, 2-aminopyrrolidine derivative 15, aminolactone derivative 16, and azasugar analogues 17 and 18. When carbon nucleophiles were used, alkaloid precursors such as 2-allyl- or 2-alkylpyrrolidines 19-23 and 25 were obtained.
- Boto, Alicia,Hernandez, Rosendo,Suarez, Ernesto
-
p. 4930 - 4937
(2007/10/03)
-
- Chirospecific synthesis of trans-2,5-disubstituted pyrrolidines via stereoselective addition of organocopper reagents to N-acyliminium ions
-
Reaction of the N-acyliminium ion precursor 1a (derived from S-proline via anodic methoxylation) with RCu in the presence of BF3·Et2O gives preferentially the trans adducts 2 (trans:cis ≥96:4). Using such a procedure, a general synthetic route to (2R, 5R)-trans-2,5-dialkylpyrrolidines has been developed, as exemplified by the chirospecific syntheses of the ant feromones trans 5-butyl-2-heptylpyrrolidine (10a), trans-5-ethyl-2-heptylpyrrolidine (10b) and trans-5-heptyl-2-(5-hexenyl)pyrrolidine (10c).
- Wistrand, Lars-G.,Skrinjar, Marco
-
p. 573 - 582
(2007/10/02)
-
- Syntheses of Substituted L- and D-Tryptophans
-
Several 5-substituted nb-methoxycarbonyl-L- and -D-tryptophan derivatives were synthesized from proline by a new route involving electrochemical oxidation, as well as by the known procedures.Removal of the Nb-methoxycarbonyl group was accomplished by treatment with Me3SiI in refluxing chloroform, then alkaline hydrolysis of the methyl esters afforded 5-substituted L- and D-tryptophans with high optical purities.Keywords - L-tryptophan 5-substituted; D-tryptophan 5-substituted; anodic oxidation; N-methoxycarbonyl group deprotection; Fischer indole synthesis; iodotrimethylsilane
- Irie, Kunihiko,Ishida, Akihiko,Nakamura, Tohru,Oh-ishi, Tokuro
-
p. 2126 - 2139
(2007/10/02)
-
- VALIDITY OF METHOXYCARBONYL AS AN N-PROTECTING GROUP IN PEPTIDE SYNTHESIS: NEW SYNTHESIS OF MSH-RELEASE INHIBITING FACTOR
-
N-Methoxycarbonyl (MOC)-amino acids regenerate the parent amino acids by treatment with dimethyl sulphide and methanesulphonic acid.Synthesis of MSH-Release Inhibiting Factor was accomplished using MOC-amino acids and applying the above mentioned deblocking method.
- Irie, Hiroshi,Nakanishi, Hiromi,Fujii, Nobutaka,Mizuno, Yukio,Fushimi, Tamaki,et al.
-
p. 705 - 708
(2007/10/02)
-