Design and synthesis of potent dual inhibitors of JAK2 and HDAC based on fusing the pharmacophores of XL019 and vorinostat

被引:38
作者
Chu-Farseeva, Yu-yi [1 ]
Mustafa, Nurulhuda [2 ]
Poulsen, Anders [3 ]
Tan, Eng Chong [4 ]
Yen, Jeffrey J. Y. [4 ]
Chng, Wee Joo [2 ,5 ,6 ]
Dymock, Brian W. [1 ]
机构
[1] Natl Univ Singapore, Dept Pharm, Singapore, Singapore
[2] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Med, 1E Kent Ridge Rd,NUHS Tower,Block Level 10, Singapore 119228, Singapore
[3] Expt Therapeut Ctr, 31 Biopolis Way,03-01 Nanos, Singapore 138669, Singapore
[4] Acad Sinica, Inst Biomed Sci, Taipei, Taiwan
[5] Natl Univ Singapore, Canc Sci Inst, Singapore 117599, Singapore
[6] Natl Univ Hlth Syst, Natl Univ Canc Inst Singapore, Singapore 119074, Singapore
基金
新加坡国家研究基金会; 英国医学研究理事会;
关键词
Multicomponent ligand; JAK2; inhibitor; HDAC inhibitor; JAK/HDAC dual inhibitor; KINASE; 2; JAK2; CELL-LINES; DEACETYLASE; SB1518; RUXOLITINIB; COMBINATION; DISCOVERY; APOPTOSIS; LYMPHOMA; THERAPY;
D O I
10.1016/j.ejmech.2018.09.024
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
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. (C) 2018 Elsevier Masson SAS. All rights reserved.
引用
收藏
页码:593 / 619
页数:27
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