- The Importance of Being Me: Magic Methyls, Methyltransferase Inhibitors, and the Discovery of Tazemetostat
-
Posttranslational methylation of histones plays a critical role in gene regulation. Misregulation of histone methylation can lead to oncogenic transformation. Enhancer of Zeste homologue 2 (EZH2) methylates histone 3 at lysine 27 (H3K27) and abnormal methylation of this site is found in many cancers. Tazemetostat, an EHZ2 inhibitor in clinical development, has shown activity in both preclinical models of cancer as well as in patients with lymphoma or INI1-deficient solid tumors. Herein we report the structure-activity relationships from identification of an initial hit in a high-throughput screen through selection of tazemetostat for clinical development. The importance of several methyl groups to the potency of the inhibitors is highlighted as well as the importance of balancing pharmacokinetic properties with potency.
- Kuntz, Kevin W.,Campbell, John E.,Keilhack, Heike,Pollock, Roy M.,Knutson, Sarah K.,Porter-Scott, Margaret,Richon, Victoria M.,Sneeringer, Chris J.,Wigle, Tim J.,Allain, Christina J.,Majer, Christina R.,Moyer, Mikel P.,Copeland, Robert A.,Chesworth, Richard
-
p. 1556 - 1564
(2016/03/05)
-
- EZH2 INHIBITORS AND USES THEREOF
-
The present disclosure provides compounds of any one of Formulae (I) and (II). The compounds described herein are inhibitors of histone methyltransferases (e.g., enhancer of zeste homolog 1 (EZH1) and enhancer of zeste homolog 2 (EZH2)) and are useful in treating and/or preventing a broad range of diseases (e.g., proliferative diseases). Also provided in the present disclosure are pharmaceutical compositions, kits, methods, and uses including or using a compound described herein. Further provided in the present disclosure are methods of identifying EZH1and/or EZH2 inhibitors.
- -
-
Paragraph 00355
(2016/07/05)
-
- USE OF COMPOSITIONS MODULATING CHROMATIN STRUCTURE FOR GRAFT VERSUS HOST DISEASE (GVHD)
-
In some aspects, the instant disclosure relates to methods of treating chronic graft versus host disease (cGVHD). In some embodiments, the method comprises administering to a subject in need thereof a EZH2 inhibitor, a Bcl6 inhibitor and/or BRD4 inhibitor. The present disclosure is based, at least in part, on the discovery that enhancer of zeste homolog 2 (EZH2) inhibitors, B-cell lymphoma 6 protein (Bcl6) inhibitors and/or bromodomain-containing protein 4 (BRD4) inhibitors can be used to treat chronic graft versus host disease (cGVHD).
- -
-
-
- AZAINDAZOLES
-
Herein are disclosed azaindazoles of formula (I), (I), where the various groups are defined herein, and which are useful for treating cancer.
- -
-
-
- Approach to the library of fused pyridine-4-carboxylic acids by combes-type reaction of acyl pyruvates and electron-rich amino heterocycles
-
A library of fused pyridine-4-carboxylic acids (including pyrazolo[3,4-b]pyridines, isoxazolo[5,4-b]pyridines, furo[2,3-b]pyridines, thieno[2,3-b]pyridines, and pyrido[2,3-d]pyrimidines) was generated by Combes-type reaction of acyl pyruvates and electron-rich amino heterocycles followed by hydrolysis of the ester. The library members were also demonstrated to undergo the standard combinatorial transformations including amide coupling and esterification, as well as less common heterocyclizations to 1,2,4-triazoles and 1,2,4-oxadiazoles.
- Volochnyuk, Dmitriy M.,Ryabukhin, Sergey V.,Plaskon, Andrey S.,Dmytriv, Yuri V.,Grygorenko, Oleksandr O.,Mykhailiuk, Pavel K.,Krotko, Dmitriy G.,Pushechnikov, Alexei,Tolmachev, Andrey A.
-
scheme or table
p. 510 - 517
(2010/09/05)
-
- PYRIMIDINES WITH TIE2 (TEK) ACTIVITY
-
The invention relates to a compound of the Formula (I). or salt thereof wherein R1, R2, R3, R4, R5, R6, A, B, L, n and m are as defined in the description. The invention also relates to pharmaceutical compositions of said compounds, the use of said compounds as medicaments and in the production of an anti-angiogenic effect in a warm-blooded animal. The invention also relates to processes for the preparation of said compounds.
- -
-
Page/Page column 161
(2010/02/12)
-
- Studies on 3'-quaternary ammonium cephalosporins-IV. Synthesis and antibacterial activity of 3'-(2-alkyl-3-aminopyrazolium)cephalosporins related to FK037
-
The synthesis and in vitro antibacterial activity of 7β-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido] cephalosporins bearing various 2-alkyl-3-aminopyrazolium groups at the 3-position are described. Antibacterial activity against MRSA was affected by the nature of the substituent at the 2-position on the 3'-aminopyrazolium groups. Among the cephalosporins prepared in this study, 7β-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[3-amino-2-(2 -hydroxyethyl)-pyrazolio]methyl-3-cephem-4-carboxylate sulfate (23e, FK037) showed extremely potent broad-spectrum activity against both Gram-positive bacteria including MRSA, and Gram-negative bacteria including Pseudomonas aeruginosa. In particular, the in vivo activity against MRSA of FK037 was the highest of all the β-lactam antibiotics tested.
- Ohki, Hidenori,Kawabata, Kohji,Inamoto, Yoshiko,Okuda, Shinya,Kamimura, Toshiaki,Sakane, Kazuo
-
p. 1685 - 1694
(2007/10/03)
-
