RAS 家族 GTP 酶是人类癌症中最常见突变的癌基因家族。近 20% 的人类肿瘤中发现了三种 RAS 亚型（HRAS、KRAS 或 NRAS）中任意一种的激活突变，而 NRAS 突变则出现在约 25% 的黑色素瘤中。尽管针对突变 KRAS 的治疗取得了显着进展，但仍缺乏 NRAS 特异性药理学。因此，NRAS抑制剂的开发将解决治疗携带NRAS突变的原发性肿瘤以及BRAF突变黑色素瘤的关键未满足需求，这些肿瘤经常通过NRAS突变对临床批准的BRAF抑制剂产生耐药性。基于我们之前对识别 HRAS 和 KRAS 但不识别 NRAS 的单体 NS1 的研究，我们在此报告了一种单体的开发，该单体可以特异性结合 NRAS 的 GDP 和 GTP 结合状态，并在突变不可知的情况下抑制 NRAS 介导的信号传导方式。此外，该单体可以被格式化为基因编码的 NRAS 特异性降解剂。我们的研究强调了开发 NRAS 选择性抑制剂用于治疗的可行性。© 2024。这是美国政府的作品，在美国不受版权保护；可能适用外国版权保护。

The RAS family GTPases are the most frequently mutated oncogene family in human cancers. Activating mutations in either of the three RAS isoforms (HRAS, KRAS, or NRAS) are found in nearly 20% of all human tumors with NRAS mutated in ~25% of melanomas. Despite remarkable advancements in therapies targeted against mutant KRAS, NRAS-specific pharmacologics are lacking. Thus, development of inhibitors of NRAS would address a critical unmet need to treating primary tumors harboring NRAS mutations as well as BRAF-mutant melanomas, which frequently develop resistance to clinically approved BRAF inhibitors through NRAS mutation. Building upon our previous studies with the monobody NS1 that recognizes HRAS and KRAS but not NRAS, here we report the development of a monobody that specifically binds to both GDP and GTP-bound states of NRAS and inhibits NRAS-mediated signaling in a mutation-agnostic manner. Further, this monobody can be formatted into a genetically encoded NRAS-specific degrader. Our study highlights the feasibility of developing NRAS selective inhibitors for therapeutic efforts.© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.