Noronha Glenn, Cao Jianguo, Chow Chun P, Dneprovskaia Elena, Fine Richard M, Hood John, Kang Xinshan, Klebansky Boris, Lohse Dan, Mak Chi Ching, McPherson Andre, Palanki Moorthy S S, Pathak Ved P, Renick Joel, Soll Richard, Zeng Binqi
TargeGen, Inc., 9380 Judicial Drive, San Diego, CA 92121, USA.
Curr Top Med Chem. 2008;8(10):905-21. doi: 10.2174/156802608784911635.
Chronic myelogenous leukemia (CML) is a hematological stem cell disorder caused by increased and unregulated growth of myeloid cells in the bone marrow, and the accumulation of excessive white blood cells. Abelson tyrosine kinase (ABL) is a non-receptor tyrosine kinase involved in cell growth and proliferation and is usually under tight control. However, 95% of CML patients have the ABL gene from chromosome 9 fused with the breakpoint cluster (BCR) gene from chromosome 22, resulting in a short chromosome known as the Philadelphia chromosome. This Philadelphia chromosome is responsible for the production of BCR-ABL, a constitutively active tyrosine kinase that causes uncontrolled cellular proliferation. An ABL inhibitor, imatinib, was approved by the FDA for the treatment of CML, and is currently used as first line therapy. However, a high percentage of clinical relapse has been observed due to long term treatment with imatinib. A majority of these relapsed patients have several point mutations at and around the ATP binding pocket of the ABL kinase domain in BCR-ABL. In order to address the resistance of mutated BCR-ABL to imatinib, 2(nd) generation inhibitors such as dasatinib, and nilotinib were developed. These compounds were approved for the treatment of CML patients who are resistant to imatinib. All of the BCR-ABL mutants are inhibited by the 2(nd) generation inhibitors with the exception of the T315I mutant. Several 3(rd) generation inhibitors such as AP24534, VX-680 (MK-0457), PHA-739358, PPY-A, XL-228, SGX-70393, FTY720 and TG101113 are being developed to target the T315I mutation. The early results from these compounds are encouraging and it is anticipated that physicians will have additional drugs at their disposal for the treatment of patients with the mutated BCR-ABL-T315I. The success of these inhibitors has greater implication not only in CML, but also in other diseases driven by kinases where the mutated gatekeeper residue plays a major role.
慢性粒细胞白血病（CML）是一种血液干细胞疾病，由骨髓中髓系细胞过度且不受调控地生长以及过量白细胞的积累所致。阿贝尔森酪氨酸激酶（ABL）是一种参与细胞生长和增殖的非受体酪氨酸激酶，通常处于严格调控之下。然而，95%的慢性粒细胞白血病患者的9号染色体上的ABL基因与22号染色体上的断裂簇区域（BCR）基因融合，形成一种名为费城染色体的短染色体。这种费城染色体负责产生BCR-ABL，一种组成型活性酪氨酸激酶，可导致细胞不受控制地增殖。一种ABL抑制剂伊马替尼已获美国食品药品监督管理局（FDA）批准用于治疗慢性粒细胞白血病，目前用作一线治疗药物。然而，由于长期使用伊马替尼治疗，已观察到较高比例的临床复发情况。这些复发患者中的大多数在BCR-ABL的ABL激酶结构域的ATP结合口袋及其周围存在多个点突变。为了解决突变型BCR-ABL对伊马替尼的耐药性问题，开发了第二代抑制剂，如达沙替尼和尼罗替尼。这些化合物已获批准用于治疗对伊马替尼耐药的慢性粒细胞白血病患者。除T315I突变体外，所有BCR-ABL突变体均被第二代抑制剂抑制。正在开发几种第三代抑制剂，如AP24534、VX-680（MK-0457）、PHA-739358、PPY-A、XL-228、SGX-70393、FTY720和TG101113，以靶向T315I突变。这些化合物的早期结果令人鼓舞，预计医生将有更多药物可用于治疗携带突变型BCR-ABL-T315I的患者。这些抑制剂的成功不仅对慢性粒细胞白血病意义重大，对其他由激酶驱动且突变的守门残基起主要作用的疾病也具有更大的意义。
