皮肤鳞状细胞癌（cSCC）是第二常见的皮肤癌。尽管 cSCC 会导致高危个体的显着发病率和死亡率，但部署其他有效的 cSCC 化学预防措施却受到毒性的限制。我们的系统计算药物再利用筛选预测，selumetinib（一种 MAPK（丝裂原激活蛋白激酶）激酶抑制剂 (MEKi)）将逆转与 cSCC 发展相关的转录特征，这与我们暗示 MEK 作为化学预防靶点的基因组分析一致。虽然全身性 MEKi 可以抑制小鼠 cSCC 的形成，但全身性 MEKi 可能会引起严重的副作用。在此，我们报告了一种代谢不稳定的 MEKi NFX-179 的开发，该药物旨在在体循环中快速代谢之前有效且选择性地抑制皮肤中的 MAPK 通路。 NFX-179 的鉴定基于其生化和细胞效力、选择性以及全身吸收后的快速代谢。在我们的紫外线诱导 cSCC 小鼠模型中，局部应用 NFX-179 凝胶在 0.1% 或更高剂量下，28 天时新 cSCC 的形成平均减少 60%。我们在另一项分割小鼠随机对照研究中进一步证实了这些效应的局部性质，其中仅在药物治疗区域观察到 cSCC 的抑制。没有观察到毒性。 NFX-179 以剂量依赖性方式抑制人 SCC 细胞系的生长，局部应用 NFX-179 会渗透人体皮肤并抑制人 cSCC 外植体中的 MAPK 信号传导。总之，我们的数据为通过应用 NFX-179 凝胶使用局部 MEK 抑制作为 cSCC 化学预防的有效策略提供了令人信服的理由。

Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer. Although cSCC contributes to substantial morbidity and mortality in high-risk individuals, deployment of otherwise effective chemoprevention of cSCC is limited by toxicities. Our systematic computational drug repurposing screen predicted that selumetinib, a MAPK (mitogen-activated protein kinase) kinase inhibitor (MEKi), would reverse transcriptional signatures associated with cSCC development, consistent with our genomic analysis implicating MEK as a chemoprevention target. Although systemic MEKi suppresses the formation of cSCC in mice, systemic MEKi can cause severe adverse effects. Here, we report the development of a metabolically labile MEKi, NFX-179, designed to potently and selectively suppress the MAPK pathway in the skin before rapid metabolism in the systemic circulation. NFX-179 was identified on the basis of its biochemical and cellular potency, selectivity, and rapid metabolism upon systemic absorption. In our ultraviolet-induced cSCC mouse model, topical application of NFX-179 gel reduced the formation of new cSCCs by an average of 60% at doses of 0.1% and greater at 28 days. We further confirmed the localized nature of these effects in an additional split-mouse randomized controlled study where suppression of cSCC was observed only in drug-treated areas. No toxicities were observed. NFX-179 inhibits the growth of human SCC cell lines in a dose-dependent manner, and topical NFX-179 application penetrates human skin and inhibits MAPK signaling in human cSCC explants. Together, our data provide a compelling rationale for using topical MEK inhibition through the application of NFX-179 gel as an effective strategy for cSCC chemoprevention.