Sheehan J Roadnight, de Wijn Astrid S, Friedman Ran
Department of Mechanical and Industrial Engineering, Norwegian University of Science and Technology, Trondheim, Norway.
Department of Chemistry and Biomedical Sciences, Linnaeus University, Kalmar, Sweden.
Protein Sci. 2025 Aug;34(8):e70219. doi: 10.1002/pro.70219.
Despite continuous strides forward in drug development, resistance to treatment looms large in the battle against cancer as well as communicable diseases. Chronic myeloid leukemia (CML) is treated with targeted therapy and treatment is personalized when resistance arises. It has been extensively studied and is used as a model for targeted therapy. In this study, we examine combination treatments of type II Abl1 inhibitors and asciminib (an allosteric regulator) through a computational model at patient relevant concentrations. Due to the separate binding sites of type II inhibitors and asciminib, we propose their combination treatment as potentially robust to resistance. We find that the simultaneous cobinding of type II inhibitors and asciminib is high in synergetic combinations. As an aid to designing and comparing combination treatments, we put forward an equation that expands on the previously published effective ratio of IC (ERIC). Unlike usual comparisons of IC values, ERIC takes patient plasma concentrations into account. This study shows that the product of two ERIC values ( ) creates comparable approximations of the effectiveness of combination treatments with low levels of synergy or antagonism at different concentrations. Its simple formulation is done without experiments and requires less computation and input data than the current standard of ZIP values. As such, the new scheme is a useful complement to experiments that deal with synergy in drug use.
尽管在药物研发方面不断取得进展，但在对抗癌症和传染病的斗争中，治疗耐药性问题依然严峻。慢性粒细胞白血病（CML）采用靶向治疗，出现耐药时治疗方案会个性化定制。CML已得到广泛研究，并被用作靶向治疗的模型。在本研究中，我们通过一个计算模型，在与患者相关的浓度下研究II型Abl1抑制剂与阿塞西尼布（一种变构调节剂）的联合治疗。由于II型抑制剂和阿塞西尼布的结合位点不同，我们提出它们的联合治疗可能对耐药具有较强的抗性。我们发现，在协同组合中，II型抑制剂和阿塞西尼布的同时共结合程度很高。为了辅助设计和比较联合治疗方案，我们提出了一个方程，该方程是在先前发表的IC有效比（ERIC）基础上扩展而来的。与通常对IC值的比较不同，ERIC考虑了患者血浆浓度。本研究表明，两个ERIC值（ ）的乘积能对不同浓度下具有低水平协同或拮抗作用的联合治疗效果产生可比的近似值。其简单的公式无需实验即可得出，与当前的ZIP值标准相比，所需的计算和输入数据更少。因此，新方案是处理药物使用中协同作用实验的有用补充。
