Drugging an undruggable pocket on KRAS
Drugging an undruggable pocket on KRAS
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DOI：
10.1073/pnas.1904529116
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发表时间：
2019-08-06
影响因子：
11.1
通讯作者：
McConnell, Darryl B.
中科院分区：
文献类型：
--
作者：
Kessler, Dirk;Gmachl, Michael;McConnell, Darryl B.
3种人RAS基因，KRAS、NRAS和HRAS，编码4种不同的RAS蛋白，其属于小GTP酶的蛋白质家族，其作为参与细胞信号传导的二元分子开关起作用。RAS中的激活突变是人类癌症中最常见的致癌驱动因素之一，其中KRAS是最常突变的致癌基因。尽管KRAS是许多癌症的优秀药物发现靶点，尽管经过数十年的研究，但尚未有直接靶向RAS的治疗药物获得临床批准。使用基于结构的药物设计，我们发现BI-2852（1）是一种KRAS抑制剂，以纳摩尔亲和力与RAS上开关I和II之间的口袋结合，迄今为止被认为是“不可用药的”; 1在机制上不同于共价KRAS（G12 C）抑制剂，因为它与KRAS活性和非活性形式中存在的不同口袋结合。在此过程中，它阻断了所有GEF、GAP和效应子与KRAS的相互作用，导致下游信号传导的抑制和KRAS突变细胞中低微摩尔范围内的抗增殖作用。这些发现清楚地表明，这种所谓的开关I/II口袋确实是可药物化的，并为科学界提供了一种化学探针，可以同时靶向KRAS的活性和非活性形式。
The 3 human RAS genes, KRAS, NRAS, and HRAS, encode 4 different RAS proteins which belong to the protein family of small GTPases that function as binary molecular switches involved in cell signaling. Activating mutations in RAS are among the most common oncogenic drivers in human cancers, with KRAS being the most frequently mutated oncogene. Although KRAS is an excellent drug discovery target for many cancers, and despite decades of research, no therapeutic agent directly targeting RAS has been clinically approved. Using structure-based drug design, we have discovered BI-2852 (1), a KRAS inhibitor that binds with nanomolar affinity to a pocket, thus far perceived to be "undruggable," between switch I and II on RAS; 1 is mechanistically distinct from covalent KRAS(G12C) inhibitors because it binds to a different pocket present in both the active and inactive forms of KRAS. In doing so, it blocks all GEF, GAP, and effector interactions with KRAS, leading to inhibition of downstream signaling and an antiproliferative effect in the low micromolar range in KRAS mutant cells. These findings clearly demonstrate that this so-called switch I/II pocket is indeed druggable and provide the scientific community with a chemical probe that simultaneously targets the active and inactive forms of KRAS.