尽管精准肿瘤学取得了巨大进步，但适应性耐药机制限制了分子靶向药物的长期有效性。在这里，我们评估了 MTX-531 的药理学特征，该药物经过计算设计，选择性地靶向两个关键耐药驱动因素：表皮生长因子受体和磷脂酰肌醇 3-OH 激酶 (PI3K)。 MTX-531 对这两个靶标均表现出低纳摩尔效力，并具有通过共晶结构分析预测的高度特异性。 MTX-531单一疗法一致导致鳞状头颈患者来源的异种移植（PDX）模型的肿瘤消退。 MTX-531 与丝裂原激活蛋白激酶激酶或 KRAS-G12C 抑制剂的组合导致 BRAF 突变或 KRAS 突变结直肠癌 PDX 模型持久消退，导致中位生存期显着增加。 MTX-531 在小鼠体内的耐受性非常好，而且不会导致 PI3K 抑制剂常见的高血糖现象。在这里，我们证明 MTX-531 是过氧化物酶体增殖物激活受体-γ 的弱激动剂，这一属性可能减轻 PI3K 抑制引起的高血糖。 MTX-531 的这一独特功能赋予了 PI3K 抑制剂通常不具备的良好治疗指数。© 2024。作者。

Despite tremendous progress in precision oncology, adaptive resistance mechanisms limit the long-term effectiveness of molecularly targeted agents. Here we evaluated the pharmacological profile of MTX-531 that was computationally designed to selectively target two key resistance drivers, epidermal growth factor receptor and phosphatidylinositol 3-OH kinase (PI3K). MTX-531 exhibits low-nanomolar potency against both targets with a high degree of specificity predicted by cocrystal structural analyses. MTX-531 monotherapy uniformly resulted in tumor regressions of squamous head and neck patient-derived xenograft (PDX) models. The combination of MTX-531 with mitogen-activated protein kinase kinase or KRAS-G12C inhibitors led to durable regressions of BRAF-mutant or KRAS-mutant colorectal cancer PDX models, resulting in striking increases in median survival. MTX-531 is exceptionally well tolerated in mice and uniquely does not lead to the hyperglycemia commonly seen with PI3K inhibitors. Here, we show that MTX-531 acts as a weak agonist of peroxisome proliferator-activated receptor-γ, an attribute that likely mitigates hyperglycemia induced by PI3K inhibition. This unique feature of MTX-531 confers a favorable therapeutic index not typically seen with PI3K inhibitors.© 2024. The Author(s).