Concomitant Inhibition of PI3Kβ and BRAF or MEK in PTEN-Deficient/BRAF-Mutant Melanoma Treatment: Preclinical Assessment of SAR260301 Oral PI3Kβ-Selective Inhibitor

Mol Cancer Ther. 2016 Jul;15(7):1460-71. doi: 10.1158/1535-7163.MCT-15-0496. Epub 2016 May 12.


Class IA PI3K pathway activation resulting from PTEN deficiency has been associated with lack of sensitivity of melanoma to BRAF kinase inhibitors. Although previous studies have shown synergistic activity when pan-PI3K inhibitors were combined with MAPK inhibitors in the treatment of melanoma exhibiting concurrent genetic abnormalities, overlapping adverse events in patients limit optimal dosing and clinical application. With the aim of specifically targeting PTEN-deficient cancers and minimizing the potential for on-target toxicity when inhibiting multiple PI3K isoforms, we developed a program to discover PI3Kβ-selective kinase inhibitors and identified SAR260301 as a potent PI3Kβ-selective, orally available compound, which is now in clinical development. Herein, we provide a detailed biological characterization of SAR260301, and show that this compound has outstanding biochemical and cellular selectivity for the PI3Kβ isoform versus the α, δ, and γ isoforms and a large panel of protein and lipid kinases. We demonstrate that SAR260301 blocks PI3K pathway signaling preferentially in PTEN-deficient human tumor models, and has synergistic antitumor activity when combined with vemurafenib (BRAF inhibitor) or selumetinib (MEK inhibitor) in PTEN-deficient/BRAF-mutated human melanoma tumor models. Combination treatments were very well tolerated, suggesting the potential for a superior safety profile at optimal dosing using selective compounds to inhibit multiple signaling pathways. Together, these experiments provide a preclinical proof-of-concept for safely combining inhibitors of PI3Kβ and BRAF or MEK kinase modulators to improve antitumor activity in PTEN-deficient/BRAF-mutant melanoma, and support the evaluation of SAR260301-based combinations in clinical studies. Mol Cancer Ther; 15(7); 1460-71. ©2016 AACR.

MeSH terms

  • Administration, Oral
  • Animals
  • Cell Line, Tumor
  • Class Ia Phosphatidylinositol 3-Kinase / chemistry
  • Disease Models, Animal
  • Drug Synergism
  • Female
  • Humans
  • Indoles / administration & dosage
  • Indoles / chemistry
  • Indoles / pharmacology*
  • MAP Kinase Kinase 1 / antagonists & inhibitors*
  • MAP Kinase Signaling System / drug effects
  • Melanoma / drug therapy
  • Melanoma / genetics*
  • Melanoma / metabolism*
  • Melanoma / pathology
  • Mice
  • Models, Molecular
  • Molecular Conformation
  • Mutation*
  • PTEN Phosphohydrolase / deficiency*
  • Phosphoinositide-3 Kinase Inhibitors*
  • Protein Binding
  • Protein Kinase Inhibitors / pharmacology
  • Proto-Oncogene Proteins B-raf / antagonists & inhibitors*
  • Proto-Oncogene Proteins B-raf / genetics*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Pyrimidinones / administration & dosage
  • Pyrimidinones / chemistry
  • Pyrimidinones / pharmacology*
  • Signal Transduction / drug effects
  • Xenograft Model Antitumor Assays


  • 2-(2-(2-methyl-2,3-dihydroindol-1-yl)-2-oxoethyl)-6-morpholin-4-yl-3H-pyrimidin-4-one
  • Indoles
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Kinase Inhibitors
  • Pyrimidinones
  • Class Ia Phosphatidylinositol 3-Kinase
  • Proto-Oncogene Proteins B-raf
  • Proto-Oncogene Proteins c-akt
  • MAP Kinase Kinase 1
  • PTEN Phosphohydrolase
  • PTEN protein, human