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 cancer in adults. Despite aggressive local treatments for primary UM, metastasis frequently occurs, and effective options for metastatic disease are limited. Genetic analyses of UM samples have identified mutually exclusive activating mutations in the Gq alpha subunits GNAQ and GNA11. One of the primary downstream targets of these constitutively active Gq alpha subunits is the protein kinase C (PKC) signaling pathway.

In this context, we report the discovery of darovasertib (NVP-LXS196), a potent pan-PKC inhibitor with high selectivity across the entire kinome. The lead compound was optimized for both kinase and off-target selectivity, resulting in a drug that is rapidly absorbed and well tolerated in preclinical models. Darovasertib is currently being investigated in clinical trials as a monotherapy and in combination with other therapies for the treatment of uveal melanoma, including both primary UM LXS-196 and metastatic uveal melanoma (MUM).