3 research outputs found
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)
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)
Allosteric Inhibition of SHP2: Identification of a Potent, Selective, and Orally Efficacious Phosphatase Inhibitor
SHP2
is a nonreceptor protein tyrosine phosphatase (PTP) encoded by the <i>PTPN11</i> gene involved in cell growth and differentiation
via the MAPK signaling pathway. SHP2 also purportedly plays an important
role in the programmed cell death pathway (PD-1/PD-L1). Because it
is an oncoprotein associated with multiple cancer-related diseases,
as well as a potential immunomodulator, controlling SHP2 activity
is of significant therapeutic interest. Recently in our laboratories,
a small molecule inhibitor of SHP2 was identified as an allosteric
modulator that stabilizes the autoinhibited conformation of SHP2.
A high throughput screen was performed to identify progressable chemical
matter, and X-ray crystallography revealed the location of binding
in a previously undisclosed allosteric binding pocket. Structure-based
drug design was employed to optimize for SHP2 inhibition, and several
new protein–ligand interactions were characterized. These studies
culminated in the discovery of 6-(4-amino-4-methylpiperidin-1-yl)-3-(2,3-dichlorophenyl)Âpyrazin-2-amine
(SHP099, <b>1</b>), a potent, selective, orally bioavailable,
and efficacious SHP2 inhibitor