Alkynylnicotinamide‐Based Compounds as ABL1 Inhibitors with Potent Activities against Drug‐Resistant CML Harboring ABL1(T315I) Mutant Kinase,ChemMedChem

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Alkynylnicotinamide‐Based Compounds as ABL1 Inhibitors with Potent Activities against Drug‐Resistant CML Harboring ABL1(T315I) Mutant Kinase
ChemMedChem ( IF 3.6 ) Pub Date : 2018-05-22 , DOI: 10.1002/cmdc.201700829
Elizabeth A Larocque ₁ , N Naganna ₁ , Clement Opoku-Temeng _{1,

2} , Alyssa M Lambrecht ₁ , Herman O Sintim ₁

Affiliation

The introduction of imatinib into the clinical scene revolutionized the treatment of chronic myelogenous leukemia (CML). The overall eight‐year survival rate for CML has increased from about 6 % in the 1970s to over 90 % in the imatinib era. However, about 20 % of CML patients harbor primary or acquired resistance to tyrosine kinase inhibitors. ABL1 point mutations in the BCR‐ABL1 fusion protein, such as ABL1(T315I), typically emerge after prolonged kinase inhibitor treatment. Ponatinib (AP24534) is currently the only approved CML drug that is active against the ABL1(T315I) mutation. However, ponatinib has severe cardiovascular toxicities; hence, there have been efforts to find safer CML drugs that work against ABL1 secondary mutations. We reveal that isoquinoline‐ or naphthyridine‐based compounds, such as HSN431, HSN576, HSN459, and HSN608 potently inhibit the enzymatic activities of ABL1, ABL1(T315I), and ABL1(E255K). These compounds inhibit the proliferation of ABL1‐driven CML cell lines, K652 and KCL22 as well as the drug‐resistant cell line, KCL22‐IR, which harbors the secondary mutated ABL1(T315I) kinase.

中文翻译：

基于炔基烟酰胺的化合物作为 ABL1 抑制剂，对携带 ABL1(T315I) 突变激酶的耐药 CML 具有有效活性

伊马替尼引入临床彻底改变了慢性粒细胞白血病（CML）的治疗。 CML 的总体八年生存率已从 20 世纪 70 年代的约 6% 提高到伊马替尼时代的 90% 以上。然而，约 20% 的 CML 患者对酪氨酸激酶抑制剂具有原发性或获得性耐药性。 BCR-ABL1 融合蛋白中的 ABL1 点突变（例如 ABL1(T315I)）通常在长期激酶抑制剂治疗后出现。 Ponatinib (AP24534) 是目前唯一批准的对 ABL1(T315I) 突变具有活性的 CML 药物。然而，ponatinib有严重的心血管毒性；因此，人们一直在努力寻找针对 ABL1 二次突变的更安全的 CML 药物。我们发现异喹啉或萘啶基化合物，如 HSN431、HSN576、HSN459 和 HSN608 有效抑制 ABL1、ABL1(T315I) 和 ABL1(E255K) 的酶活性。这些化合物抑制 ABL1 驱动的 CML 细胞系 K652 和 KCL22 以及耐药细胞系 KCL22-IR 的增殖，该细胞系含有二次突变的 ABL1(T315I) 激酶。

更新日期：2018-05-22

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