Synthesis and structure-activity relationships of dual PI3K/mTOR inhibitors based on a 4-amino-6-methyl-1,3,5-triazine sulfonamide scaffold

Ryan P Wurz; Longbin Liu; Kevin Yang; Nobuko Nishimura; Yunxin Bo; Liping H Pettus; Sean Caenepeel; Daniel J Freeman; John D McCarter; Erin L Mullady; Tisha San Miguel; Ling Wang; Nancy Zhang; Kristin L Andrews; Douglas A Whittington; Jian Jiang; Raju Subramanian; Paul E Hughes; Mark H Norman

doi:10.1016/j.bmcl.2012.06.078

Synthesis and structure-activity relationships of dual PI3K/mTOR inhibitors based on a 4-amino-6-methyl-1,3,5-triazine sulfonamide scaffold

Bioorg Med Chem Lett. 2012 Sep 1;22(17):5714-20. doi: 10.1016/j.bmcl.2012.06.078. Epub 2012 Jul 3.

Affiliation

¹ Department of Chemistry Research & Discovery, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA. rwurz@amgen.com

PMID: 22832322
DOI: 10.1016/j.bmcl.2012.06.078

Abstract

Phosphoinositide 3-kinase (PI3K) is an important target in oncology due to the deregulation of the PI3K/Akt signaling pathway in a wide variety of tumors. A series of 4-amino-6-methyl-1,3,5-triazine sulfonamides were synthesized and evaluated as inhibitors of PI3K. The synthesis, in vitro biological activities, pharmacokinetic and in vivo pharmacodynamic profiling of these compounds are described. The most promising compound from this investigation (compound 3j) was found to be a pan class I PI3K inhibitor with a moderate (>10-fold) selectivity over the mammalian target of rapamycin (mTOR) in the enzyme assay. In a U87 MG cellular assay measuring phosphorylation of Akt, compound 3j displayed low double digit nanomolar IC(50) and exhibited good oral bioavailability in rats (F(oral)=63%). Compound 3j also showed a dose dependent reduction in the phosphorylation of Akt in a U87 tumor pharmacodynamic model with a plasma EC(50)=193 nM (91 ng/mL).

MeSH terms

Animals
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacokinetics
Antineoplastic Agents / pharmacology
Antineoplastic Agents / therapeutic use
Binding Sites
Cell Line, Tumor
Crystallography, X-Ray
Female
Humans
Mice
Molecular Docking Simulation
Neoplasms / drug therapy*
Neoplasms / enzymology
Neoplasms / metabolism
Phosphatidylinositol 3-Kinases / chemistry
Phosphatidylinositol 3-Kinases / metabolism
Phosphoinositide-3 Kinase Inhibitors*
Phosphorylation / drug effects
Protein Kinase Inhibitors / chemistry*
Protein Kinase Inhibitors / pharmacokinetics
Protein Kinase Inhibitors / pharmacology*
Protein Kinase Inhibitors / therapeutic use
Proto-Oncogene Proteins c-akt / metabolism
Rats
Signal Transduction / drug effects
Structure-Activity Relationship
Sulfonamides / chemistry*
Sulfonamides / pharmacokinetics
Sulfonamides / pharmacology*
Sulfonamides / therapeutic use
TOR Serine-Threonine Kinases / antagonists & inhibitors*
TOR Serine-Threonine Kinases / metabolism
Triazines / chemistry
Triazines / pharmacokinetics
Triazines / pharmacology
Triazines / therapeutic use

Substances

Antineoplastic Agents
Phosphoinositide-3 Kinase Inhibitors
Protein Kinase Inhibitors
Sulfonamides
Triazines
Proto-Oncogene Proteins c-akt
TOR Serine-Threonine Kinases