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Hsp90 Inhibitors for the Treatment of Chronic Myeloid Leukemia

机译：Hsp90抑制剂治疗慢性粒细胞白血病

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Chronic myeloid leukemia (CML) is a hematological malignancy that arises due to reciprocal translocation of 3′ sequences from c-Abelson (ABL) protooncogene of chromosome 9 with 5′ sequence of truncated break point cluster region (BCR) on chromosome 22. BCR-ABL is a functional oncoprotein p210 that exhibits constitutively activated tyrosine kinase causing genomic alteration of hematopoietic stem cells. BCR-ABL specific tyrosine kinase inhibitors (TKIs) successfully block CML progression. However, drug resistance owing to BCR-ABL mutations and overexpression is still an issue. Heat-shock proteins (Hsps) function as molecular chaperones facilitating proper folding of nascent polypeptides. Their increased expression under stressful conditions protects cells by stabilizing unfolded or misfolded peptides. Hsp90 is the major mammalian protein and is required by BCR-ABL for stabilization and maturation. Hsp90 inhibitors destabilize the binding of BCR-ABL protein thus leading to the formation of heteroprotein complex that is eventually degraded by the ubiquitin-proteasome pathway. Results of many novel Hsp90 inhibitors that have entered into various clinical trials are encouraging. The present review targets the current development in the CML treatment by availing Hsp90 specific inhibitors.
机译：慢性粒细胞白血病（CML）是由于9号染色体的c-Abelson（ABL）原癌基因3'序列与22号染色体的截断点簇区域（BCR）的5'序列相互易位引起的血液系统恶性肿瘤。 ABL是一种功能性癌蛋白p210，它具有构成性激活的酪氨酸激酶，可引起造血干细胞的基因组改变。 BCR-ABL特异性酪氨酸激酶抑制剂（TKIs）成功阻止CML进展。但是，由于BCR-ABL突变和过表达引起的耐药性仍然是一个问题。热休克蛋白（Hsps）充当分子伴侣，促进新生多肽的正确折叠。它们在应激条件下的表达增加，通过稳定未折叠或错误折叠的肽来保护细胞。 Hsp90是主要的哺乳动物蛋白，是BCR-ABL稳定和成熟所必需的。 Hsp90抑制剂使BCR-ABL蛋白的结合不稳定，从而导致形成异蛋白复合物，该复合物最终会被泛素-蛋白酶体途径降解。已经进入各种临床试验的许多新型Hsp90抑制剂的结果令人鼓舞。本综述通过利用Hsp90特异性抑制剂来针对CML治疗的当前发展。

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