Discovery of Darovasertib (NVP-LXS196), a Pan-PKC Inhibitor for the Treatment of Metastatic Uveal Melanoma.
Michael VisserJulien P N PapillonMichael LuzzioMatthew J LaMarcheJianmei FanWalter MichaelDavid WangAlan ZhangChristopher StraubSimon MathieuMitsunori KatoMark PalermoChristine ChenTimothy RamseyCarol JoudRosemary BarrettAnthony VattayRibo GuoAnka BricFranklin ChungGuiqing LiangMichael J RomanowskiJoni LamSanjeev ThohanFaraj AtassiAndrew WylieVesselina G CookePublished in: Journal of medicinal chemistry (2024)
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).
Keyphrases
- protein kinase
- signaling pathway
- small cell lung cancer
- squamous cell carcinoma
- small molecule
- skin cancer
- high throughput
- primary care
- stem cells
- pi k akt
- dna methylation
- mesenchymal stem cells
- clinical trial
- epithelial mesenchymal transition
- gene expression
- oxidative stress
- open label
- high resolution
- induced apoptosis
- single molecule
- high speed
- atomic force microscopy