Reengineering Ponatinib to Minimize Cardiovascular Toxicity
Reengineering Ponatinib to Minimize Cardiovascular Toxicity
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DOI：
10.1158/0008-5472.can-21-365
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发表时间：
2022-08-01
期刊：
影响因子：
11.2
通讯作者：
Mercola, Mark
中科院分区：
文献类型：
--
作者：
Hnatiuk, Anna P.;Bruyneel, Arne A. N.;Mercola, Mark
小分子酪氨酸激酶抑制剂（TKI）的出现使肿瘤治疗发生了革命性的变化，大大提高了患者的生存率。然而，许多TKI的危及生命的心脏毒性已成为一个主要问题。Ponatinib（ICLUSIG）是作为BCR-ABL癌基因抑制剂开发的，是心脏毒性最强的TKI之一。因此，泊那替尼的使用仅限于治疗携带T315 I突变BCR-ABL的肿瘤，这种肿瘤发生在慢性髓性白血病（CML）中，并对第一代和第二代抑制剂（如伊马替尼和尼洛替尼）产生耐药性。通过心血管毒性和抗肿瘤疗效试验的平行筛选，我们设计了更安全的泊那替尼类似物，保留了对T315 I BCR-ABL激酶活性的效力，并抑制了T315 I突变型CML肿瘤生长。新化合物在体外人心脏血管生成和心肌细胞收缩试验中毒性显著降低。这些化合物在体内显示出更大的治疗窗口，导致人T315 I突变型CML异种移植物消退而没有心脏毒性。泊那替尼和新化合物的激酶抑制特征的比较表明，泊那替尼的心脏毒性是由一些激酶介导的，其中一些以前与心血管疾病无关。总的来说，该研究开发了一种使用复杂表型测定的方法，以降低小分子肿瘤治疗中普遍存在的心血管毒性的高风险。重要性：新开发的泊那替尼类似物保留了抗肿瘤疗效，但引起的心脏毒性显著降低，代表了更安全的CML治疗的治疗机会。
Small molecule tyrosine kinase inhibitors (TKI) have revo-lutionized cancer treatment and greatly improved patient sur-vival. However, life-threatening cardiotoxicity of many TKIs has become a major concern. Ponatinib (ICLUSIG) was developed as an inhibitor of the BCR-ABL oncogene and is among the most cardiotoxic of TKIs. Consequently, use of ponatinib is restricted to the treatment of tumors carrying T315I-mutated BCR-ABL, which occurs in chronic myeloid leukemia (CML) and confers resistance to first-and second-generation inhibitors such as imatinib and nilotinib. Through parallel screening of cardio-vascular toxicity and antitumor efficacy assays, we engineered safer analogs of ponatinib that retained potency against T315I BCR-ABL kinase activity and suppressed T315I mutant CML tumor growth. The new compounds were substantially less toxic in human cardiac vasculogenesis and cardiomyocyte contrac-tility assays in vitro. The compounds showed a larger therapeutic window in vivo, leading to regression of human T315I mutant CML xenografts without cardiotoxicity. Comparison of the kinase inhibition profiles of ponatinib and the new compounds suggested that ponatinib cardiotoxicity is mediated by a few kinases, some of which were previously unassociated with cardiovascular disease. Overall, the study develops an approach using complex phenotypic assays to reduce the high risk of cardiovascular toxicity that is prevalent among small molecule oncology therapeutics. Significance: Newly developed ponatinib analogs retain antitumor efficacy but elicit significantly decreased cardiotoxicity, representing a therapeutic opportunity for safer CML treatment.