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).