Reengineering Ponatinib to Minimize Cardiovascular Toxicity.
Reengineering Ponatinib to Minimize Cardiovascular Toxicity.
复制标题
重新设计波纳替尼以将心血管毒性降至最低。
DOI：
10.1158/0008-5472.can-21-3652
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发表时间：
2022-08-03
期刊：
影响因子：
11.2
通讯作者：
Mercola, Mark
中科院分区：
文献类型：
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作者：
Hnatiuk, Anna P.;Bruyneel, Arne A. N.;Tailor, Dhanir;Pandrala, Mallesh;Dheeraj, Arpit;Li, Wenqi;Serrano, Ricardo;Feyen, Dries A. M.;Vu, Michelle M.;Amatya, Prashila;Gupta, Saloni;Nakauchi, Yusuke;Morgado, Isabel;Wiebking, Volker;Liao, Ronglih;Porteus, Matthew H.;Majeti, Ravindra;Malhotra, Sanjay, V;Mercola, Mark
新开发的波纳替尼类似物保持了抗肿瘤效果，但显著降低了心脏毒性，为更安全的CML治疗提供了治疗机会。小分子酪氨酸激酶抑制剂(TKI)使癌症治疗发生了革命性的变化，极大地提高了患者的存活率。然而，许多TKI危及生命的心脏毒性已成为人们关注的主要问题。波纳替尼(Iclusig)是作为bcr-abl癌基因的抑制剂而开发的，是TKI中心脏毒性最强的药物之一。因此，Ponatinib的使用仅限于治疗携带T315I突变的bcr-abl的肿瘤，这种肿瘤发生在慢性粒细胞白血病(CML)中，并对第一代和第二代抑制剂如伊马替尼和尼洛替尼具有耐药性。通过心血管毒性和抗肿瘤疗效的平行筛选，我们设计出了更安全的Ponatinib类似物，它保留了对T315I bcr-abl激酶活性的效力，并抑制了T315I突变的CML肿瘤生长。新化合物在体外的人体心脏血管生成和心肌细胞收缩能力测试中毒性显著较低。这些化合物在体内显示出更大的治疗窗口，导致无心脏毒性的人T315I突变CML异种移植的消退。比较波纳替尼和新化合物的激酶抑制谱表明，波纳替尼的心脏毒性是由几种激酶介导的，其中一些以前与心血管疾病无关。总体而言，这项研究开发了一种使用复杂的表型分析来降低在小分子肿瘤治疗中普遍存在的心血管毒性的高风险的方法。新开发的波纳替尼类似物保持了抗肿瘤效果，但显著降低了心脏毒性，为更安全的CML治疗提供了治疗机会。
Newly developed ponatinib analogs retain antitumor efficacy but elicit significantly decreased cardiotoxicity, representing a therapeutic opportunity for safer CML treatment. Small molecule tyrosine kinase inhibitors (TKI) have revolutionized cancer treatment and greatly improved patient survival. 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 cardiovascular 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 contractility 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. Newly developed ponatinib analogs retain antitumor efficacy but elicit significantly decreased cardiotoxicity, representing a therapeutic opportunity for safer CML treatment.