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一种首创的 EGFR 和 PI3K 选择性抑制剂为靶向适应性耐药提供了一种单一分子的方法。

A first-in-class selective inhibitor of EGFR and PI3K offers a single-molecule approach to targeting adaptive resistance.

机构信息

Department of Radiology, University of Michigan, Ann Arbor, MI, USA.

MEKanistic Therapeutics, Inc., Ann Arbor, MI, USA.

出版信息

Nat Cancer. 2024 Aug;5(8):1250-1266. doi: 10.1038/s43018-024-00781-6. Epub 2024 Jul 11.

DOI:10.1038/s43018-024-00781-6
PMID:38992135
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11357990/
Abstract

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.

摘要

尽管在精准肿瘤学方面取得了巨大进展，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 的药理学特性，它是通过计算设计来选择性靶向两个关键的耐药驱动因素，即表皮生长因子受体和磷脂酰肌醇 3-激酶（PI3K）。MTX-531 对这两个靶点均表现出低纳摩尔效力，其高特异性通过共晶结构分析预测。MTX-531 单药治疗均导致鳞状头颈部患者来源异种移植（PDX）模型的肿瘤消退。MTX-531 与丝裂原活化蛋白激酶激酶或 KRAS-G12C 抑制剂联合使用，导致 BRAF 突变或 KRAS 突变结直肠癌 PDX 模型的持久消退，中位生存期显著延长。MTX-531 在小鼠中具有极好的耐受性，并且不会导致通常与 PI3K 抑制剂相关的高血糖。在这里，我们表明 MTX-531 作为过氧化物酶体增殖物激活受体-γ的弱激动剂起作用，这一特性可能减轻了 PI3K 抑制引起的高血糖。MTX-531 的这种独特特征赋予了通常与 PI3K 抑制剂不同的有利治疗指数。

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