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

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).

Citation

Michael Visser, Julien P N Papillon, Michael Luzzio, Matthew J LaMarche, Jianmei Fan, Walter Michael, David Wang, Alan Zhang, Christopher Straub, Simon Mathieu, Mitsunori Kato, Mark Palermo, Christine Chen, Timothy Ramsey, Carol Joud, Rosemary Barrett, Anthony Vattay, Ribo Guo, Anka Bric, Franklin Chung, Guiqing Liang, Michael J Romanowski, Joni Lam, Sanjeev Thohan, Faraj Atassi, Andrew Wylie, Vesselina G Cooke. Discovery of Darovasertib (NVP-LXS196), a Pan-PKC Inhibitor for the Treatment of Metastatic Uveal Melanoma. Journal of medicinal chemistry. 2024 Jan 25;67(2):1447-1459

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PMID: 38198520

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