Excessive concentrations of kinase inhibitors in translational studies impede effective drug repurposing.
Excessive concentrations of kinase inhibitors in translational studies impede effective drug repurposing.
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DOI：
10.1016/j.xcrm.2023.101227
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发表时间：
2023-10-17
影响因子：
14.3
通讯作者：
Pritchard, Justin R.
中科院分区：
文献类型：
--
作者：
Liu, Chuan;Leighow, Scott M.;Mcilroy, Kyle;Lu, Mengrou;Dennis, Kady A.;Abello, Kerry;Brown, Donovan J.;Moore, Connor J.;Shah, Anushka;Inam, Haider;Rivera, Victor M.;Pritchard, Justin R.
药物重新定位旨在利用现有的临床知识来确定批准药物的替代临床环境。然而，重新定位的努力未能证明在后期临床试验中成功率的提高。集中在11个批准的激酶抑制剂，已在139个重新定位的假设进行了评估，我们使用数据挖掘来表征临床再利用的状态。然后，使用一个简单的实验校正与人血清蛋白在体外药效学测定，我们开发了一种药物的有效暴露的测量。我们表明，这个指标是显着预测的临床活性的五个激酶抑制剂的面板在白血病的23个药物变体的目标。然后，我们验证了我们的模型在两种类型的实体瘤：非小细胞肺癌（NSCLC）和胃肠道间质瘤（GIST）的其他六种激酶抑制剂中的性能。我们的方法提出了一个简单的策略，利用现有的临床信息和实验系统，以减少药物再利用研究的临床失败率。临床药物再利用努力容易失败有效的药物暴露准确地预测了抑制剂在靶向变体中的疗效在白血病数据上训练的模型被验证用于肺癌和GIST Effective Cave可以从体外数据预测临床再利用努力的成功Liu et al.开发一种度量有效的药物安全性-易于确定，并从体外数据预测抑制剂的疗效。所提出的框架可用于在未来的转化研究中选择药物浓度，以提高临床再利用工作的成功率。
Drug repositioning seeks to leverage existing clinical knowledge to identify alternative clinical settings for approved drugs. However, repositioning efforts fail to demonstrate improved success rates in late-stage clinical trials. Focusing on 11 approved kinase inhibitors that have been evaluated in 139 repositioning hypotheses, we use data mining to characterize the state of clinical repurposing. Then, using a simple experimental correction with human serum proteins in in vitro pharmacodynamic assays, we develop a measurement of a drug’s effective exposure. We show that this metric is remarkably predictive of clinical activity for a panel of five kinase inhibitors across 23 drug variant targets in leukemia. We then validate our model’s performance in six other kinase inhibitors for two types of solid tumors: non-small cell lung cancer (NSCLC) and gastrointestinal stromal tumors (GISTs). Our approach presents a straightforward strategy to use existing clinical information and experimental systems to decrease the clinical failure rate in drug repurposing studies. Clinical drug repurposing efforts are prone to failure Effective drug exposure accurately predicts inhibitor efficacy across target variants A model trained on leukemia data is validated for lung cancer and GISTs Effective Cave can predict success of clinical repurposing efforts from in vitro data Liu et al. develop a metric—effective drug exposure—that is easily determined and predicts inhibitor efficacy from in vitro data. The presented framework can be used to inform selection of drug concentrations in future translational studies to improve the success of clinical repurposing efforts.
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影响因子：
--
作者：
Eastman A
通讯作者：
Eastman A
伊马替尼治疗新发 1 型糖尿病患者：一项多中心、随机、双盲、安慰剂对照 2 期试验。
DOI：
10.1016/s2213-8587(21)00139-x
发表时间：
2021-08
期刊：
The lancet. Diabetes & endocrinology
影响因子：
--
作者：
Gitelman SE;Bundy BN;Ferrannini E;Lim N;Blanchfield JL;DiMeglio LA;Felner EI;Gaglia JL;Gottlieb PA;Long SA;Mari A;Mirmira RG;Raskin P;Sanda S;Tsalikian E;Wentworth JM;Willi SM;Krischer JP;Bluestone JA;Gleevec Trial Study Group
通讯作者：
Gleevec Trial Study Group
影响因子：
6.2
作者：
Araujo JC;Mathew P;Armstrong AJ;Braud EL;Posadas E;Lonberg M;Gallick GE;Trudel GC;Paliwal P;Agrawal S;Logothetis CJ
通讯作者：
Logothetis CJ
影响因子：
158.5
作者：
Kantarjian, Hagop;Giles, Francis;Ottmann, Oliver G.
通讯作者：
Ottmann, Oliver G.
影响因子：
7.3
作者：
Liu, Xingrong;Wright, Matthew;Hop, Cornelis E. C. A.
通讯作者：
Hop, Cornelis E. C. A.