EasySep™小鼠TIL（CD45）正选试剂盒
产品号 #73542_C
JAK/STAT通路抑制剂；抑制JAK3
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总览
WHI-P131是Janus激酶3（JAK3）的抑制剂，对人和小鼠蛋白的IC₅₀值分别为9和78 μM（Sudbeck et al.）。据报道，它还显示出对其他激酶的显著抑制，包括nM范围内的表皮生长因子受体（EGFR）（Changelian et al.; Uckun et al.）。尚未观察到对JAK1或JAK2的显著抑制（Sudbeck et al.）。
癌症研究
·诱导人胶质母细胞瘤细胞系U373和U87的细胞凋亡和死亡（Narla et al.）。
免疫学
·抑制脂多糖（LPS）诱导的一氧化氮合酶表达和巨噬细胞中的一氧化氮生成（Sareila et al.）。
维持培养
·在低于抑制星形胶质细胞培养物增殖所需浓度的浓度下抑制含有神经干细胞的神经球的增殖（Diamandis et al.）。
细胞类型
癌细胞及细胞系，单核细胞，神经干/祖细胞
种属
人，小鼠，非人灵长类，其他物种，大鼠
研究领域
癌症，免疫
CAS 编号
202475-60-3
化学式
C₁₆H₁₅N₃O₃
纯度
≥98%
通路
JAK/STAT
靶点
JAK3
产品说明书及文档
请在《产品说明书》中查找相关支持信息和使用说明，或浏览下方更多实验方案。
相关材料与文献
技术资料 (3)
文献 (6)
Structure-based design of specific inhibitors of Janus kinase 3 as apoptosis-inducing antileukemic agents.
Clinical cancer research : an official journal of the American Association for Cancer Research 1999
Abstract
A novel homology model of the kinase domain of Janus kinase (JAK) 3 was used for the structure-based design of dimethoxyquinazoline compounds with potent and specific inhibitory activity against JAK3. The active site of JAK3 in this homology model measures roughly 8 A x 11 A x 20 A,with a volume of approximately 530 A3 available for inhibitor binding. Modeling studies indicated that 4-(phenyl)-amino-6,7-dimethoxyquinazoline (parent compound WHI-258) would likely fit into the catalytic site of JAK3 and that derivatives of this compound that contain an OH group at the 4' position of the phenyl ring would more strongly bind to JAK3 because of added interactions with Asp-967,a key residue in the catalytic site of JAK3. These predictions were consistent with docking studies indicating that compounds containing a 4'-OH group,WHI-P131 [4-(4'-hydroxyphenyl)-amino-6,7-dimethoxyquinazoline],WHI-P154 [4-(3'-bromo-4'-hydroxylphenyl)-amino-6,7-dimethoxyquinazoline],and WHI-P97 [4-(3',5'-dibromo-4'-hydroxylphenyl)-amino-6,7-dimethoxyquinazolin e],were likely to bind favorably to JAK3,with estimated K(i)s ranging from 0.6 to 2.3 microM. These compounds inhibited JAK3 in immune complex kinase assays in a dose-dependent fashion. In contrast,compounds lacking the 4'-OH group,WHI-P79 [4-(3'-bromophenyl)-amino-6,7-dimethoxyquinazoline],WHI-P111 [4-(3'-bromo-4'-methylphenyl)-amino-6,7-dimethoxyquinazoline],WHI-P112 [4-(2',5'-dibromophenyl)-amino-6,7-dimethoxyquinazoline],WHI-P132 [4-(2'-hydroxylphenyl)-amino-6,7-dimethoxyquinazoline],and WHI-P258 [4-(phenyl)-amino-6,7-dimethoxyquinazoline],were predicted to bind less strongly,with estimated K(i)s ranging from 28 to 72 microM. These compounds did not show any significant JAK3 inhibition in kinase assays. Furthermore,the lead dimethoxyquinazoline compound,WHI-P131,which showed potent JAK3-inhibitory activity (IC50 of 78 microM),did not inhibit JAK1 and JAK2,the ZAP/SYK family tyrosine kinase SYK,the TEC family tyrosine kinase BTK,the SRC family tyrosine kinase LYN,or the receptor family tyrosine kinase insulin receptor kinase,even at concentrations as high as 350 microM. WHI-P131 induced apoptosis in JAK3-expressing human leukemia cell lines NALM-6 and LC1;19 but not in melanoma (M24-MET) or squamous carcinoma (SQ20B) cells. Leukemia cells were not killed by dimethoxyquinazoline compounds that were inactive against JAK3. WHI-P131 inhibited the clonogenic growth of JAK3-positive leukemia cell lines DAUDI,RAMOS,LC1;19,NALM-6,MOLT-3,and HL-60 (but not JAK3-negative BT-20 breast cancer,M24-MET melanoma,or SQ20B squamous carcinoma cell lines) in a concentration-dependent fashion. Potent and specific inhibitors of JAK3 such as WHI-P131 may provide the basis for the design of new treatment strategies against acute lymphoblastic leukemia,the most common form of childhood cancer.
Structure-based design of novel anticancer agents.
Current cancer drug targets 2001
Abstract
Recently identified agents that interact with cytoskeletal elements such as tubulin include synthetic spiroketal pyrans (SPIKET) and monotetrahydrofuran compounds (COBRA compounds). SPIKET compounds target the spongistatin binding site of beta-tubulin and COBRA compounds target a unique binding cavity on alpha-tubulin. At nanomolar concentrations,the SPIKET compound SPIKET-P causes tubulin depolymerization and exhibits potent cytotoxic activity against cancer cells. COBRA-1 inhibits GTP-induced tubulin polymerization. Treatment of human breast cancer and brain tumor cells with COBRA-1 caused destruction of microtubule organization and apoptosis. Other studies have identified some promising protein tyrosine kinase inhibitors as anti-cancer agents. These include EGFR inhibitors such as the quinazoline derivative WHI-P97 and the leflunomide metabolite analog LFM-A12. Both LFM-A12 and WHI-P97 inhibit the in vitro invasiveness of EGFR positive human breast cancer cells at micromolar concentrations and induce apoptotic cell death. Dimethoxyquinazoline compounds WHI-P131 and WHI-P154 inhibit tyrosine kinase JAK3 in leukemia cells. Of particular interest is WHI-P131,which inhibits JAK3 but not JAK1,JAK2,SYK,BTK,LYN,or IRK at concentrations as high as 350 microM. Studies of BTK inhibitors showed that the leflunomide metabolite analog LFM-A13 inhibited BTK in leukemia and lymphoma cells. Consistent with the anti-apoptotic function of BTK,treatment of leukemic cells with LFM-A13 enhanced their sensitivity to chemotherapy-induced apoptosis.
Chemical genetics reveals a complex functional ground state of neural stem cells.
Nature chemical biology 2007
Abstract
The identification of self-renewing and multipotent neural stem cells (NSCs) in the mammalian brain holds promise for the treatment of neurological diseases and has yielded new insight into brain cancer. However,the complete repertoire of signaling pathways that governs the proliferation and self-renewal of NSCs,which we refer to as the 'ground state',remains largely uncharacterized. Although the candidate gene approach has uncovered vital pathways in NSC biology,so far only a few highly studied pathways have been investigated. Based on the intimate relationship between NSC self-renewal and neurosphere proliferation,we undertook a chemical genetic screen for inhibitors of neurosphere proliferation in order to probe the operational circuitry of the NSC. The screen recovered small molecules known to affect neurotransmission pathways previously thought to operate primarily in the mature central nervous system; these compounds also had potent inhibitory effects on cultures enriched for brain cancer stem cells. These results suggest that clinically approved neuromodulators may remodel the mature central nervous system and find application in the treatment of brain cancer.
更多信息
| 物种 | 人, 其它物种, 大鼠, 小鼠, 非人灵长类 |
|---|---|
| Cas Number | 202475-60-3 |
| Chemical Formula | C₁₆H₁₅N₃O₃ |
| 纯度 | ≥ 98% |
| Target | JAK3 |
| Pathway | JAK/STAT |
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