文献

APIM050045: Darovasertib (LXS-196, IDE-196) is a potent, selective and orally active protein kinase C (PKC) inhibitor, with IC₅₀ values of 1.9 nM, 0.4 nM and 3.1 μM for PKCα, PKCθ and GSK3β, respectively. Darovasertib has the potential for uveal melanoma research.

CAS No.: 1874276-76-2
IUPAC/Chemical Name: 3-amino-N-(3-(4-amino-4-methylpiperidin-1-yl)pyridin-2-yl)-6-(3-(trifluoromethyl)pyridin-2-yl)pyrazine-2-carboxamide
Molecular Formula: C₂₂H₂₃F₃N₈O
Molecular Weight: 472.48
Purity: 99.9% by HPLC
QC: Achiral and Chiral HPLCs, MS, NMR, and Quantitative Elemental Analysis Report
Solubility: Soluble in DMSO
Storage: Dry, dark and at 0 – 4 C for short term (days to weeks) or -20 C for long term (months to years).
Note: Please contact us for COA, Spectra, and SDS information.

Background Information:

Uveal melanoma (UM) is the most common primary intraocular tumor. The majority (>90%) of uveal melanoma harbor activating mutations in the GNAQ and GNA11 Ga subunits of G protein coupled receptors. These genetic driver mutations, which are also detected in other solid tumors, lead to continuous activation of protein kinase C (PKC) and downstream signaling pathways such as the mitogen-activated protein kinase (MAPK) signaling pathway. Inhibition of PKC with small molecule inhibitors is an attractive therapeutic approach in UM. Darovasertib (LXS-196, IDE-196) is a selective and potent protein kinase C inhibitor targeting the novel (δ, ε, η, θ) and classical (α, β) PKC isoforms and has shown anti-tumor activity as monotherapy in patients with metastatic uveal melanoma (MUM). Inhibiting downstream signaling pathways in addition to PKC inhibition with Darovasertib (LXS-196, IDE-196) may increase the anti-tumor activity in MUM patients. Modulation of PKC, MAPK pathway activity and other downstream markers were assessed by WB. The evaluated uveal melanoma cell lines expressed different phospho-PKC isoforms and were sensitive to increasing concentrations of Darovasertib (LXS-196, IDE-196) as demonstrated by decreased levels of PKC substrate p-MARCKS and reduced cell viability. Combination of Darovasertib (LXS-196, IDE-196) with MEK inhibitors Binimetinib or Trametinib showed synergy at clinically relevant doses for each compound. The observed synergy of Darovasertib (LXS-196, IDE-196) with MEK inhibitors is further substantiated by modulation of MARCKS and MAPK pathway activity as measured by WB.

Target: PKCα, PKCθ, GSK3β

IC₅₀: 1.9 nM (PKCα), 0.4 nM (PKCθ), 3.1 μM (GSK3β)

In Vitro: Upon oral administration, protein kinase C inhibitor Darovasertib (LXS-196) binds to and inhibits PKC, which prevents the activation of PKC-mediated signaling pathways. This may lead to the induction of cell cycle arrest and apoptosis in susceptible tumor cells. PKC, a serine/threonine protein kinase overexpressed in certain types of cancer cells, is involved in tumor cell differentiation, proliferation, invasion and survival. [1]

In Vivo: Darovasertib (LXS-196) (15, 30, 75, 150 mg/kg, P.O., mice) shows improved efficacy (regression) in a 92.1 GNAQ uveal melanoma xenograft model in a dose-dependently manner. [1]

What is the solubility of Darovasertib (LXS-196) (CAS No. 1874276-76-2) in vitro?
DMSO: > 25 mg/mL

What is the solubility of Darovasertib (LXS-196) (CAS No. 1874276-76-2) in vivo?
1. DMSO, PEG300, Tween-80, and saline
Please add 10% DMSO, 40% PEG300, 5% Tween-80, and 45% saline in order, solubility: ≥ 2.5 mg/mL.
2. DMSO and 20% SBE-β-CD in saline
Please add 10% DMSO and 90% (20% SBE-β-CD in saline) in order, solubility: ≥ 2.5 mg/mL.
3. DMSO and corn oil
Please add 10% DMSO and 90% corn oil in order, solubility: ≥ 2.5 mg/mL.

Reference:
[1]. Frey, C. R. et al. “Abstract 5337: Analysis of drug combinations with the PKC inhibitor IDE196 support dual MEK and PKC inhibition as a rational combination in metastatic uveal melanoma”, Cancer Res., 2020, DOI: 10.1158/1538-7445.AM2020-5337.
[2]. Shoushtari, A. N. et al. “A Phase Ib Study of Sotrastaurin, a PKC Inhibitor, and Alpelisib, a PI3Kα Inhibitor, in Patients with Metastatic Uveal Melanoma”, Cancers (Basel), 2021, 13, 5504. doi: 10.3390/cancers13215504.