Discovery of Darovasertib (NVP-LXS196), a Pan-PKC Inhibitor for the Treatment of Metastatic Uveal Melanoma,Journal of Medicinal Chemistry

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Discovery of Darovasertib (NVP-LXS196), a Pan-PKC Inhibitor for the Treatment of Metastatic Uveal Melanoma
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-01-10 , DOI: 10.1021/acs.jmedchem.3c02002
Michael Visser ₁ , Julien P N Papillon ₁ , Michael Luzzio ₁ , Matthew J LaMarche ₁ , Jianmei Fan ₁ , Walter Michael ₁ , David Wang ₁ , Alan Zhang ₁ , Christopher Straub ₁ , Simon Mathieu ₁ , Mitsunori Kato ₁ , Mark Palermo ₁ , Christine Chen ₁ , Timothy Ramsey ₁ , Carol Joud ₁ , Rosemary Barrett ₁ , Anthony Vattay ₁ , Ribo Guo ₁ , Anka Bric ₁ , Franklin Chung ₁ , Guiqing Liang ₁ , Michael J Romanowski ₁ , Joni Lam ₁ , Sanjeev Thohan ₁ , Faraj Atassi ₁ , Andrew Wylie ₁ , Vesselina G Cooke ₁

Affiliation

Uveal melanoma (UM) is the most common primary intraocular malignancy in the adult eye. Despite the aggressive local management of primary UM, the development of metastases is common with no effective treatment options for metastatic disease. Genetic analysis of UM samples reveals the presence of mutually exclusive activating mutations in the Gq alpha subunits GNAQ and GNA11. One of the key downstream targets of the constitutively active Gq alpha subunits is the protein kinase C (PKC) signaling pathway. Herein, we describe the discovery of darovasertib (NVP-LXS196), a potent pan-PKC inhibitor with high whole kinome selectivity. The lead series was optimized for kinase and off target selectivity to afford a compound that is rapidly absorbed and well tolerated in preclinical species. LXS196 is being investigated in the clinic as a monotherapy and in combination with other agents for the treatment of uveal melanoma (UM), including primary UM and metastatic uveal melanoma (MUM).

中文翻译：

发现 Darovasertib (NVP-LXS196)，一种用于治疗转移性葡萄膜黑色素瘤的泛 PKC 抑制剂

葡萄膜黑色素瘤（UM）是成人眼中最常见的原发性眼内恶性肿瘤。尽管对原发性 UM 进行了积极的局部治疗，但转移的发生很常见，并且没有针对转移性疾病的有效治疗方案。 UM 样本的遗传分析揭示了 Gq α 亚基 GNAQ 和 GNA11 中存在相互排斥的激活突变。组成型活性 Gq α 亚基的关键下游靶标之一是蛋白激酶 C (PKC) 信号通路。在此，我们描述了 darovasertib (NVP-LXS196) 的发现，这是一种具有高全激酶组选择性的有效泛 PKC 抑制剂。先导系列针对激酶和脱靶选择性进行了优化，以提供在临床前物种中快速吸收和良好耐受的化合物。 LXS196 正在临床中作为单一疗法以及与其他药物联合治疗葡萄膜黑色素瘤 (UM)，包括原发性 UM 和转移性葡萄膜黑色素瘤 (MUM) 进行研究。

更新日期：2024-01-10

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