一种双位点激酶抑制剂的设计方法
A design approach for bitopic kinase inhibitors
传统激酶抑制剂因只结合单一高度保守的位点，难以同时兼顾效力与选择性。双位点（bitopic）抑制剂可同时结合同一靶点上的多个位点以突破这一限制。作者以ABL1和EGFR为模型，系统探索配体选择、连接方向和连接长度等设计参数，发现效力受配体间协同性和连接子熵影响。针对ABL1（BCR::ABL1驱动白血病的重要靶点）现有药物受耐药突变和脱靶效应限制、三代抑制剂ponatinib虽克服多种耐药突变但心血管毒性限制其使用的临床难题，他们设计出PonatiLink-2，对耐药突变体保持或超过ponatinib的效力，且在体内外治疗窗口更宽，可提高剂量而不见明显毒性。在小鼠模型中，该药无论是与dasatinib联用对抗野生型BCR::ABL1，还是单药对抗ponatinib耐药疾病，均优于临床相关疗法。
为什么推荐给您：提出普适的双位点激酶抑制剂设计策略，并在小鼠模型中验证优效候选药物。
不需要生物学背景，多打比方
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摘要Abstract
Traditional kinase inhibitors face a trade-off between potency and selectivity because their affinity depends on limited molecular interactions in a single highly conserved binding site. Bitopic inhibitors overcome this limitation by engaging multiple sites on the same target1. Here, using ABL1 and EGFR as model kinases, we systematically explore the bitopic-specific design parameters of ligand choice, linkage vector and linker length and show that they affect potency through inter-ligand cooperativity and linker entropy. We apply this approach to address an unmet clinical need: existing inhibitors of ABL1, an important target in BCR::ABL1-driven leukaemias, are constrained by resistance mutations and off-target effects2. The third-generation inhibitor ponatinib overcomes many resistance mutations, but cardiovascular toxicity limits its clinical use3. We design a bitopic ABL1 inhibitor, PonatiLink-2, that maintains or surpasses the potency of ponatinib against resistance mutants. Moreover, it has an enhanced therapeutic window in vitro and in vivo, which enables increased dosing without apparent toxicity. PonatiLink-2 outperforms clinically relevant treatments in mouse models of BCR::ABL1-driven cancer, both in combination with dasatinib against wild-type BCR::ABL1 and as a single agent against ponatinib-resistant disease. These findings indicate that the bitopic design approach is a promising strategy for developing potent, well-tolerated clinical inhibitors of ABL1 and other targets.