Mutations in Kirsten rat sarcoma viral oncogene homolog (KRAS) are among the most common aberrations in cancer, including non-small cell lung cancer (NSCLC). The lack of an ideal small molecule binding pocket in the KRAS protein and its high affinity towards the abundance of cellular guanosine triphosphate (GTP) renders the design of specific small molecule drugs challenging. Despite efforts, KRAS remains a challenging therapeutic target. Among the different known mutations; the KRASG12C (glycine 12 to cysteine) mutation has been considered potentially druggable. Several novel covalent direct inhibitors targeting KRASG12C with similar covalent binding mechanisms are now in clinical trials. Both AMG 510 from Amgen and MRTX849 from Mirati Therapeutics covalently binds to KRASG12C at the cysteine at residue 12, keeping KRASG12C in its inactive GDP-bound state and inhibiting KRAS-dependent signaling. Both inhibitors are being studied as a single agent or as combination with other targets. In addition, two novel KRAS G12C inhibitors JNJ-74699157 and LY3499446 will have entered phase 1 studies by the end of 2019. Given the rapid clinical development of 4 direct covalent KRAS G12C inhibitors within a short period of time, understanding the similarities and differences among these will be important to determine the best treatment option based on tumor specific response (NSCLC versus colorectal carcinoma), potential resistance mechanisms (i.e. anticipated acquired mutation at the cysteine 12 residue) and central nervous system (CNS) activity. Additionally, further investigation evaluating the efficacy and safety of combination therapies with agents such as immune checkpoint inhibitors will be important next steps.

中文翻译：

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KRAS G12C《权力的游戏》，哪种直接 KRAS 抑制剂将登上铁王座？


克尔斯滕大鼠肉瘤病毒癌基因同源物 (KRAS) 的突变是癌症中最常见的畸变之一，包括非小细胞肺癌 (NSCLC)。 KRAS 蛋白中缺乏理想的小分子结合袋，且其对丰富的细胞三磷酸鸟苷 (GTP) 的高亲和力使得特定小分子药物的设计具有挑战性。尽管付出了努力，KRAS 仍然是一个具有挑战性的治疗靶点。在不同的已知突变中； KRASG12C（12号甘氨酸变为半胱氨酸）突变被认为具有潜在的药物作用。几种具有相似共价结合机制的针对 KRASG12C 的新型共价直接抑制剂目前正在进行临床试验。 Amgen 的 AMG 510 和 Mirati Therapeutics 的 MRTX849 均与 KRASG12C 残基 12 的半胱氨酸共价结合，使 KRASG12C 保持非活性 GDP 结合状态并抑制 KRAS 依赖性信号传导。这两种抑制剂正在作为单一药物或与其他靶点的组合进行研究。此外，两种新型KRAS G12C抑制剂JNJ-74699157和LY3499446将于2019年底进入1期研究。鉴于4种直接共价KRAS G12C抑制剂在短时间内快速临床开发，了解它们之间的异同这些对于根据肿瘤特异性反应（NSCLC 与结直肠癌）、潜在耐药机制（即半胱氨酸 12 残基的预期获得性突变）和中枢神经系统 (CNS) 活性确定最佳治疗方案非常重要。此外，进一步研究评估免疫检查点抑制剂等药物联合疗法的有效性和安全性将是下一步的重要步骤。