APS-2-79 is a KSR-dependent MAPK modulator. APS-2-79 modulates KSR-dependent MAPK signalling by antagonizing RAF heterodimerization as well as the conformational changes required for phosphorylation and activation of KSR-bound MEK (mitogen-activated protein kinase kinase). APS-2-79 increased the potency of several MEK inhibitors specifically within Ras-mutant cell lines by antagonizing release of negative feedback signalling, demonstrating the potential of targeting KSR to improve the efficacy of current MAPK inhibitors. Co-targeting of enzymatic and scaffolding activities within Ras-MAPK signalling complexes is a therapeutic strategy for overcoming Ras-driven cancers.
CAS Number: 2002381-25-9
Molecular Weight: 387.43
Chemical Name: 6,7-Dimethoxy-N-(2-methyl-4-phenoxyphenyl)quinazolin-4-amine
Appearance: Solid Power
Purity: ≥98% (or refer to the Certificate of Analysis)
Solubility: Soluble in DMSO
Shipping Condition: Shipped under ambient temperature as non-hazardous chemical or refer to Certificate of Analysis
Storage Condition: Dry, dark and -20 oC for 1 year or refer to the Certificate of Analysis.
Shelf Life: ≥12 months if stored properly.
Stock Solution Storage: 0 - 4 oC for 1 month or refer to the Certificate of Analysis.
Drug Formulation: To be determined.
HS Tariff Code: 382200
How to use
APS-2-79 (1 μM) shifts the cell viability dose response to Trametinib in Ras-mutant cell lines HCT-116 and A549, but not BRAF mutant cell lines SK-MEL-239 and A375. Although the cellular effects of APS-2-79 alone are modest, combination analysis over full concentration matrices reveal that kinase suppressor of Ras (KSR)-inactive state (KSRi) synergizes with Trametinib, and other MEK inhibitors, specifically in KRAS mutant cell lines. APS-3-77, and additional control compounds, do not demonstrate Ras-mutant-specific synergy, supporting the hypothesis that the enhanced activity of Trametinib when combined with APS-2-79 depends on co-modulation of KSR.
- KSR Mutations Guide Development of RAS Pathway Antagonists. Cancer Discov. 2016 Oct;6(10):1079. PubMed PMID: 27591198.
- Dhawan NS, Scopton AP, Dar AC. Small molecule stabilization of the KSR inactive state antagonizes oncogenic Ras signalling. Nature. 2016 Aug 24;537(7618):112-116. doi: 10.1038/nature19327. [Epub ahead of print] PubMed PMID: 27556948.
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