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

J Med Chem. 2024 Jan 25;67(2):1447-1459. doi: 10.1021/acs.jmedchem.3c02002. Epub 2024 Jan 10.

Abstract

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).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • GTP-Binding Protein alpha Subunits / genetics
  • GTP-Binding Protein alpha Subunits / metabolism
  • GTP-Binding Protein alpha Subunits, Gq-G11 / metabolism
  • Humans
  • Melanoma* / drug therapy
  • Melanoma* / pathology
  • Mutation
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use
  • Uveal Neoplasms* / drug therapy
  • Uveal Neoplasms* / metabolism

Substances

  • GTP-Binding Protein alpha Subunits
  • GTP-Binding Protein alpha Subunits, Gq-G11
  • Protein Kinase Inhibitors

Supplementary concepts

  • Uveal melanoma