- SAR and in vivo evaluation of 4-aryl-2-aminoalkylpyrimidines as potent and selective Janus kinase 2 (JAK2) inhibitors
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We report the discovery of a series of 4-aryl-2-aminoalkylpyrimidine derivatives as potent and selective JAK2 inhibitors. High throughput screening of our in-house compound library led to the identification of hit 1, from which optimization resulted in the discovery of highly potent and selective JAK2 inhibitors. Advanced lead 10d demonstrated a significant dose-dependent pharmacodynamic and antitumor effect in a mouse xenograft model. Based upon the desirable profile of 10d (XL019) it was advanced into clinical trials.
- Forsyth, Timothy,Kearney, Patrick C.,Kim, Byung Gyu,Johnson, Henry W.B.,Aay, Naing,Arcalas, Arlyn,Brown, David S.,Chan, Vicky,Chen, Jeff,Du, Hongwang,Epshteyn, Sergey,Galan, Adam A.,Huynh, Tai P.,Ibrahim, Mohamed A.,Kane, Brian,Koltun, Elena S.,Mann, Grace,Meyr, Lisa E.,Lee, Matthew S.,Lewis, Gary L.,Noguchi, Robin T.,Pack, Michael,Ridgway, Brian H.,Shi, Xian,Takeuchi, Craig S.,Zu, Peiwen,Leahy, James W.,Nuss, John M.,Aoyama, Ron,Engst, Stefan,Gendreau, Steven B.,Kassees, Robert,Li, Jia,Lin, Shwu-Hwa,Martini, Jean-Francois,Stout, Thomas,Tong, Philip,Woolfrey, John,Zhang, Wentao,Yu, Peiwen
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- Design and synthesis of potent dual inhibitors of JAK2 and HDAC based on fusing the pharmacophores of XL019 and vorinostat
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Specifically blocking more than one oncogenic pathway simultaneously in a cancer cell with a combination of different drugs is the mainstay of the majority of cancer treatments. Being able to do this via two targeted pathways without inducing side effects through a general mechanism, such as chemotherapy, could bring benefit to patients. In this work we describe a new dual inhibitor of the JAK-STAT and HDAC pathways through designing and developing two types of molecule based on the JAK2 selective inhibitor XL019 and the pan-HDAC inhibitor, vorinostat. Both series of compounds had examples with low nanomolar JAK2 and HDAC1/6 inhibition. In some cases good HDAC1 selectivity was achieved while retaining HDAC6 activity. The observed potency is explained through molecular docking studies of all three enzymes. One example, 69c had 16–25 fold selectivity against the three other JAK-family proteins JAK1, JAK3 and TYK2. A number of compounds had sub-micromolar potencies against a panel of 4 solid tumor cell lines and 4 hematological cell lines with the most potent compound, 45h, having a cellular IC50 of 70 nM against the multiple myeloma cell line KMS-12-BM. Evidence of both JAK and HDAC pathway inhibition is presented in Hela cells showing that both pathways are modulated. Evidence of apoptosis with two compounds in 4 sold tumor cell lines is also presented.
- Chu-Farseeva, Yu-yi,Mustafa, Nurulhuda,Poulsen, Anders,Tan, Eng Chong,Yen, Jeffrey J.Y.,Chng, Wee Joo,Dymock, Brian W.
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p. 593 - 619
(2018/10/02)
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- Synthesis and evaluation of the NSCLC anti-cancer activity and physical properties of 4-aryl-N-phenylpyrimidin-2-amines
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Reported herein are efforts to profile 4-aryl-N-phenylpyrimidin-2-amines in terms of their anti-cancer activity towards non small-cell lung carcinoma (NSCLC) cells. We have synthesized new 4-aryl-N-phenylpyrimidin-2-amines and assessed them in terms of their cytotoxicity (A549, NCI-H187, MCF7, Vero & KB) and physicochemical properties (logD7.4 and solubility). 13f and 13c demonstrated potent anti-cancer activity in A549 cells (0.2 μM), compared to 0.4 μM for the NSCLC drug Doxorubicin. 13f also displayed low experimental logD7.4 (2.9) and the best solubility (~40 μM). Compounds 13b and 13d showed the best balance of A549 anti-cancer activity and selectivity. 13g showed good activity and selectivity comparable with the anti-cancer drug Doxorubicin.
- Toviwek, Borvornwat,Suphakun, Praphasri,Choowongkomon, Kiattawee,Hannongbua, Supa,Gleeson, M. Paul
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supporting information
p. 4749 - 4754
(2017/09/29)
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- Optimization and biological evaluation of aminopyrimidine-based IκB kinase β inhibitors with potent anti-inflammatory effects
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Targeting IκB kinase β (IKKβ) can be a promising strategy in the development of a therapeutic treatment of inflammatory diseases because IKKβ is well-recognized as a key mediator of the NF-κB signaling pathway. In this study, we have successfully develope
- Shin, Yongje,Lim, Sang Min,Yan, Hong Hua,Jung, Sungwoo,Fang, Zhenghuan,Jung, Kyung Hee,Hong, Soon-Sun,Hong, Sungwoo
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p. 544 - 556
(2016/08/12)
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- Discovery of amide replacements that improve activity and metabolic stability of a bis-amide smoothened antagonist hit
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A bis-amide antagonist of Smoothened, a seven-transmembrane receptor in the Hedgehog signaling pathway, was discovered via high throughput screening. In vitro and in vivo experiments demonstrated that the bis-amide was susceptible to N-acyl transferase mediated amide scission. Several bioisosteric replacements of the labile amide that maintained in vitro potency were identified and shown to be metabolically stable in vitro and in vivo.
- Brown, Matthew L.,Aaron, Wade,Austin, Richard J.,Chong, Angela,Huang, Tom,Jiang, Ben,Kaizerman, Jacob A.,Lee, Gary,Lucas, Brian S.,McMinn, Dustin L.,Orf, Jessica,Rong, Minqing,Toteva, Maria M.,Xu, Guifen,Ye, Qiuping,Zhong, Wendy,Degraffenreid, Michael R.,Wickramasinghe, Dineli,Powers, Jay P.,Hungate, Randall,Johnson, Michael G.
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scheme or table
p. 5206 - 5209
(2011/10/09)
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- 4-ARYL-2-AMINO-PYRIMIDINES OR 4-ARYL-2-AMINOALKYL-PYRIMIDINES AS JAK-2 MODULATORS AND METHODS OF USE
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This invention relates to certain pyrimidine derivative inhibitors of JAK-2, having Formula (I): wherein D, E, L, Z, R1, R2, R25, and n1 are as defined in the specification, pharmaceutically acceptable salts thereof, pharmaceutical compositions thereof, and methods of use thereof.
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Page/Page column 249-250; 262-263
(2008/06/13)
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