Bafetinib，一种双 Bcr-Abl/Lyn 酪氨酸激酶抑制剂，用于治疗白血病。,Current opinion in investigational drugs (London, England : 2000)

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Bafetinib，一种双 Bcr-Abl/Lyn 酪氨酸激酶抑制剂，用于治疗白血病。
Current opinion in investigational drugs (London, England : 2000) Pub Date : 2010-12-01
Fabio P S Santos ₁ , Hagop Kantarjian , Jorge Cortes , Alfonso Quintas-Cardama

Affiliation

Bafetinib (NS-187, INNO-406) 是 CytRx 在 Nippon Shinyaku 许可下开发的第二代酪氨酸激酶抑制剂，用于治疗 Bcr-Abl + 白血病，包括慢性粒细胞白血病 (CML) 和费城 + 急性淋巴细胞白血病。它是一种基于伊马替尼化学结构合理开发的酪氨酸激酶抑制剂，并添加了修饰以提高对 Bcr-Abl 激酶的结合和效力。除 Abl 外，bafetinib 还靶向 Src 家族激酶 Lyn，该激酶与 CML 中对伊马替尼的耐药性有关。在临床前研究中，巴非替尼的体外药效比伊马替尼高 25 至 55 倍，体内药效比伊马替尼高 10 倍以上。Bafetinib 可抑制 13 种最常见的伊马替尼耐药 Bcr-Abl 点突变中的 12 种，但不能抑制 Thr315Ile 突变。一小部分 bafetinib 穿过血脑屏障，达到足以抑制 Bcr-Abl+ 细胞的脑浓度。在伊马替尼耐药或不耐受 CML 患者中进行的 I 期临床试验数据证实，巴非替尼在这种情况下具有临床活性，在这些慢性期患者中诱导了 19% 的主要细胞遗传学反应。目前，bafetinib 正在开发两项针对 B 细胞慢性淋巴细胞白血病和前列腺癌患者的 II 期临床试验，一项针对脑肿瘤患者的试验正在进行中。在 19% 的慢性期患者中诱导主要的细胞遗传学反应。目前，bafetinib 正在开发两项针对 B 细胞慢性淋巴细胞白血病和前列腺癌患者的 II 期临床试验，一项针对脑肿瘤患者的试验正在进行中。在 19% 的慢性期患者中诱导主要的细胞遗传学反应。目前，bafetinib 正在开发两项针对 B 细胞慢性淋巴细胞白血病和前列腺癌患者的 II 期临床试验，一项针对脑肿瘤患者的试验正在进行中。

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Bafetinib, a dual Bcr-Abl/Lyn tyrosine kinase inhibitor for the potential treatment of leukemia.

Bafetinib (NS-187, INNO-406) is a second-generation tyrosine kinase inhibitor in development by CytRx under license from Nippon Shinyaku for treating Bcr-Abl+ leukemia's, including chronic myelogenous leukemia (CML) and Philadelphia+ acute lymphoblastic leukemia. It is a rationally developed tyrosine kinase inhibitor based on the chemical structure of imatinib, with modifications added to improve binding and potency against Bcr-Abl kinase. Besides Abl, bafetinib targets the Src family kinase Lyn, which has been associated with resistance to imatinib in CML. In preclinical studies, bafetinib was 25- to 55-fold more potent than imatinib in vitro and ≥ 10-fold more potent in vivo. Bafetinib inhibits 12 of the 13 most frequent imatinib-resistant Bcr-Abl point mutations, but not a Thr315Ile mutation. A small fraction of bafetinib crosses the blood-brain barrier, reaching brain concentrations adequate for suppression of Bcr-Abl+ cells. Data from a phase I clinical trial conducted in patients with imatinib-resistant or -intolerant CML have confirmed that bafetinib has clinical activity in this setting, inducing a major cytogenetic response in 19% of those patients in chronic phase. Currently, bafetinib is being developed in two phase II clinical trials for patients with B-cell chronic lymphocytic leukemia and prostate cancer, and a trial is in progress for patients with brain tumors.

更新日期：2019-11-01

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