ABSTRACT

Introduction

KRAS is one of the most important oncology proteins, which can activate multiple downstream signaling pathways. Despite the prevalence of KRAS mutations in approximately 30% of human cancers, it has long been considered to be ‘undruggable’ due to the lack of recognizable binding pockets.

Areas covered

This review covers the recent patents (2019–2021) on KRAS^G12C inhibitors, which are mostly highlighted in terms of chemical structures, molecular mechanisms of action, pharmacokinetic properties, and potential clinical applications.

Expert opinion

The last 3 years have seen a significant breakthrough in the development of KRAS inhibitors. So far, ten compounds entered the clinical trials with AMG510 being approved by FDA in May 2021 for the treatment of lung cancer. Moreover, MRTX849 also holds the promise of becoming the next approved drug targeting KRAS^G12C. However, it is noteworthy that acquired resistance is expected to arise inevitably. With a potentially effective treatment on the horizon, combination strategies could further enhance the efficacy of KRAS-targeted inhibition. Whatever their strengths or limitations, emerging KRAS^G12C inhibitors will undoubtedly enrich our understanding of KRAS biology and KRAS-targeted therapy, which will shed light on the development of inhibitors targeting other KRAS mutations.

中文翻译：

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癌症中 GTPase KRASG12C 的抑制剂：专利审查 (2019-2021)

摘要

介绍

KRAS 是最重要的肿瘤蛋白之一，可激活多种下游信号通路。尽管在大约 30% 的人类癌症中普遍存在 KRAS 突变，但由于缺乏可识别的结合口袋，它长期以来一直被认为是“不可治愈的”。

涵盖的领域

这篇综述涵盖了最近关于 KRAS ^G12C抑制剂的专利（2019-2021 年），这些专利主要在化学结构、分子作用机制、药代动力学特性和潜在的临床应用方面突出。

专家意见

过去 3 年，KRAS 抑制剂的开发取得了重大突破。到目前为止，已有十种化合物进入临床试验，其中AMG510于 2021 年 5 月获得 FDA 批准用于治疗肺癌。此外，MRTX849还有望成为下一个获批的靶向 KRAS ^G12C的药物。然而，值得注意的是，获得性抗药性预计将不可避免地出现。随着潜在有效治疗的出现，联合策略可以进一步提高 KRAS 靶向抑制的功效。无论它们的优势或局限性如何，新兴的 KRAS ^G12C抑制剂无疑将丰富我们对 KRAS 生物学和 KRAS 靶向治疗的理解，这将有助于开发针对其他 KRAS 突变的抑制剂。