Selective Inhibition of the Myeloid Src-Family Kinase Fgr Potently Suppresses AML Cell Growth in Vitro and in Vivo.
Selective Inhibition of the Myeloid Src-Family Kinase Fgr Potently Suppresses AML Cell Growth in Vitro and in Vivo.
复制标题
DOI：
10.1021/acschembio.8b00154
复制
发表时间：
2018-06-15
影响因子：
4
通讯作者：
Smithgall TE
中科院分区：
文献类型：
--
作者：
Weir MC;Shu ST;Patel RK;Hellwig S;Chen L;Tan L;Gray NS;Smithgall TE
急性髓性白血病（AML）是成人中最常见的血液恶性肿瘤，通常与组成性酪氨酸激酶信号传导有关。这些途径涉及非受体酪氨酸激酶Fes、Syk和髓样细胞中表达的三种Src家族激酶（Fgr、Hck和林恩）。在这项研究中，我们报告了显着的抗AML疗效的N-苯基苯甲酰胺激酶抑制剂，TL 02 -59。该化合物有效抑制了26例AML患者中20例的骨髓样本的增殖，抑制剂敏感性与髓样Src家族激酶Fgr、Hck和林恩的表达水平之间存在显著相关性。未观察到与Flt 3表达或突变状态的相关性，其中四个最敏感的患者样品为Flt 3野生型。与体外激酶测定相结合的全激酶组靶特异性谱显示了TL 02 -59的窄的总体靶特异性谱，具有针对髓样Src家族成员Fgr的皮摩尔效力。在AML的小鼠异种移植物模型中，以10 mg/kg的剂量口服给予TL 02 -59三周，完全消除了脾和外周血中的白血病细胞，同时显著减少了骨髓植入。这些结果将Fgr鉴定为AML中先前未识别的激酶抑制剂靶标，并且将TL 02 -59鉴定为用于在不依赖于Flt 3突变的过表达该激酶的AML病例中进行临床开发的可能的先导化合物。
Acute myelogenous leukemia (AML) is the most common hematologic malignancy in adults, and is often associated with constitutive tyrosine kinase signaling. These pathways involve the non-receptor tyrosine kinases Fes, Syk and the three Src-family kinases expressed in myeloid cells (Fgr, Hck, and Lyn). In this study, we report remarkable anti-AML efficacy of an N-phenylbenzamide kinase inhibitor, TL02–59. This compound potently suppressed the proliferation of bone marrow samples from twenty of twenty-six AML patients, with a striking correlation between inhibitor sensitivity and expression levels of the myeloid Src family kinases Fgr, Hck, and Lyn. No correlation was observed with Flt3 expression or mutational status, with the four most sensitive patient samples wild-type for Flt3. Kinome-wide target specificity profiling coupled with in vitro kinase assays demonstrated a narrow overall target specificity profile for TL02–59, with picomolar potency against the myeloid Src-family member Fgr. In a mouse xenograft model of AML, oral administration of TL02–59 for three weeks at 10 mg/kg completely eliminated leukemic cells from the spleen and peripheral blood while significantly reducing bone marrow engraftment. These results identify Fgr as a previously unrecognized kinase inhibitor target in AML, and TL02–59 as a possible lead compound for clinical development in AML cases that overexpress this kinase independent of Flt3 mutations.
登录
查看更多内容
影响因子：
2.6
作者：
Robinson, LJ;Xue, J;Corey, SJ
通讯作者：
Corey, SJ
影响因子：
6.1
作者：
Pemmaraju N;Kantarjian H;Andreeff M;Cortes J;Ravandi F
通讯作者：
Ravandi F
影响因子：
17.1
作者：
Saito, Yoriko;Yuki, Hitomi;Ishikawa, Fumihiko
通讯作者：
Ishikawa, Fumihiko
影响因子：
46.9
作者：
Davis, Mindy I.;Hunt, Jeremy P.;Zarrinkar, Patrick P.
通讯作者：
Zarrinkar, Patrick P.
影响因子：
20.3
作者：
Dos Santos, Cedric;McDonald, Tinisha;Bhatia, Ravi
通讯作者：
Bhatia, Ravi