KRAS genes are the most commonly mutated oncogenes in cancer. Unfortunately, effective therapeutic strategies for targeting KRAS mutant cancers have proven to be difficult to obtain. A key reason for this setback is due to the lack of success direct KRAS mutant inhibitors have received. Researchers have turned their efforts away from targeting the KRAS nucleotide-binding site directly and towards targeting other areas of the MAPK signaling pathway to block KRAS function. Researchers found that inhibiting enzymes and protein-protein interactions involved in the MAPK signaling pathway inhibit the activation of KRAS mutant therefore can lead to a potential therapeutic for KRAS mutated cancers. Throughout the past two decades, various indirect inhibitors have been designed and tested. EGFR and MEK inhibitors have presented with less success; however, significant advances have been made when targeting the plasma membrane localization process and the allosteric site of KRAS mutant. Farnesyltransferase and allosteric inhibitors have both advanced to human clinical trials. This comprehensive review presents the most recent developments of direct and indirect KRAS mutant inhibitors. This review summarizes published data on the inhibitory and anti-cancer activity of compounds that target KRAS activation as well as highlights the most promising strategies for targeting KRAS mutant cancers.

卡拉斯基因是癌症中最常见的突变癌基因。不幸的是，已经证明难以获得靶向KRAS突变癌症的有效治疗策略。造成挫折的一个关键原因是由于缺乏成功的直接KRAS突变抑制剂。研究人员已经将他们的努力从直接靶向KRAS核苷酸结合位点转向靶向MAPK信号传导途径的其他区域来阻断KRAS功能。研究人员发现，抑制MAPK信号通路中涉及的酶和蛋白质-蛋白质相互作用会抑制KRAS突变体的激活，因此可以导致KRAS突变癌症的潜在治疗方法。在过去的二十年中，已经设计和测试了各种间接抑制剂。EGFR和MEK抑制剂的成功率较低。然而，当靶向质膜定位过程和KRAS突变体的变构位点时，已经取得了重大进展。法尼基转移酶和变构抑制剂均已进入人体临床试验。这项全面的综述介绍了直接和间接KRAS突变抑制剂的最新进展。这篇综述总结了针对靶向KRAS活化的化合物的抑制和抗癌活性的公开数据，并重点介绍了针对KRAS突变癌症的最有希望的策略。这项全面的综述介绍了直接和间接KRAS突变抑制剂的最新进展。这篇综述总结了针对靶向KRAS活化的化合物的抑制和抗癌活性的公开数据，并重点介绍了针对KRAS突变癌症的最有希望的策略。这项全面的综述介绍了直接和间接KRAS突变抑制剂的最新进展。这篇综述总结了针对靶向KRAS活化的化合物的抑制和抗癌活性的公开数据，并重点介绍了针对KRAS突变癌症的最有希望的策略。