PDF(Pubmed)
Abstract：
The FDA granted orphan drug designation to darovasertib, a first-in-class oral, small molecular inhibitor of protein kinase C (PKC), for the treatment of uveal melanoma, on 2 May 2022. Primary uveal melanoma has a high risk of progressing to metastatic uveal melanoma, with a poor prognosis. The activation of the PKC and mitogen-activated protein kinase pathways play an essential role in the pathogenesis of uveal melanoma, and mutations in the G protein subunit alpha q (GNAQ), and G protein subunit alpha11 (GNA11) genes are considered early events in the development of uveal melanoma. Compared to other PKC inhibitors, such as sotrastaurin and enzastaurin, darovasertib is significantly more potent in inhibiting conventional (α, β) and novel (δ, ϵ, η, θ) PKC proteins and has a better tolerability and safety profile. Current Phase I/II clinical trials indicated that darovasertib, combined with the Mitogen-activated protein kinase/Extracellular (MEK) inhibitors, binimetinib or crizotinib, produced a synergistic effect of uveal melanoma. In this article, we summarize the development of drugs for treating uveal melanomas and discuss problems associated with current treatments. We also discuss the mechanism of action, pharmacokinetic profile, adverse effects, and clinical trial for darovasertib, and future research directions for treating uveal melanoma.
摘要：
FDA授予darovasertib孤儿药称号，一流的口语，小分子蛋白激酶C（PKC）抑制剂，用于治疗葡萄膜黑色素瘤，2022年5月2日原发性葡萄膜黑色素瘤发展为转移性葡萄膜黑色素瘤的风险很高，预后不良。PKC和丝裂原活化蛋白激酶通路的激活在葡萄膜黑色素瘤的发病机理中起着至关重要的作用。和G蛋白亚基αq（GNAQ）的突变，G蛋白亚基α11（GNA11）基因被认为是葡萄膜黑色素瘤发展的早期事件。与其他PKC抑制剂相比，比如索特拉托林和恩扎托林，darovasertib在抑制常规(α，β)和新颖的(δ，实际上,η,θ)PKC蛋白，具有更好的耐受性和安全性。目前的I/II期临床试验表明，darovasertib，与丝裂原活化蛋白激酶/细胞外（MEK）抑制剂联合，比米替尼或克唑替尼，产生了葡萄膜黑色素瘤的协同作用。在这篇文章中,我们总结了治疗葡萄膜黑色素瘤的药物的发展，并讨论了与当前治疗相关的问题。我们还讨论了作用机制，药代动力学概况，不利影响，和darovasertib的临床试验，和未来治疗葡萄膜黑色素瘤的研究方向。
