Design, synthesis and SAR of new-di-substituted pyridopyrimidines as ATP-competitive dual PI3Kα/mTOR inhibitors

Aisha A K Al-Ashmawy; Fatma A Ragab; Khaled M Elokely; Manal M Anwar; Oscar Perez-Leal; Mario C Rico; John Gordon; Eugeney Bichenkov; George Mateo; Emad M M Kassem; Gehan H Hegazy; Magid Abou-Gharbia; Wayne Childers

doi:10.1016/j.bmcl.2017.05.044

Design, synthesis and SAR of new-di-substituted pyridopyrimidines as ATP-competitive dual PI3Kα/mTOR inhibitors

Bioorg Med Chem Lett. 2017 Jul 15;27(14):3117-3122. doi: 10.1016/j.bmcl.2017.05.044. Epub 2017 May 15.

Authors

Affiliations

¹ Moulder Center for Drug Discovery Research, Temple University, School of Pharmacy, 3307 N. Broad Street, Philadelphia, PA, USA; Department of Therapeutical Chemistry, National Research Center, Dokki, Cairo 12622, Egypt.
² Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo 11562, Egypt.
³ Department of Pharmaceutical Chemistry, Tanta University, Tanta 31527, Egypt; Department of Chemistry and ICMS, Temple University, Philadelphia 19122, PA, USA.
⁴ Department of Therapeutical Chemistry, National Research Center, Dokki, Cairo 12622, Egypt.
⁵ Moulder Center for Drug Discovery Research, Temple University, School of Pharmacy, 3307 N. Broad Street, Philadelphia, PA, USA.
⁶ Moulder Center for Drug Discovery Research, Temple University, School of Pharmacy, 3307 N. Broad Street, Philadelphia, PA, USA. Electronic address: wchilders@yahoo.com.

PMID: 28571824
DOI: 10.1016/j.bmcl.2017.05.044

Abstract

PI3Kα/mTOR ATP-competitive inhibitors are considered as one of the promising molecularly targeted cancer therapeutics. Based on lead compound A from the literature, two similar series of 2-substituted-4-morpholino-pyrido[3,2-d]pyrimidine and pyrido[2,3-d]pyrimidine analogs were designed and synthesized as PI3Kα/mTOR dual inhibitors. Interestingly, most of the series gave excellent inhibition for both enzymes with IC₅₀ values ranging from single to double digit nM. Unlike many PI3Kα/mTOR dual inhibitors, our compounds displayed selectivity for PI3Kα. Based on its potent enzyme inhibitory activity, selectivity for PI3Kα and good therapeutic index in 2D cell culture viability assays, compound 4h was chosen to be evaluated in 3D culture for its IC₅₀ against MCF7 breast cancer cells as well as for docking studies with both enzymes.

Keywords: 3-Kinase alpha; Dual inhibitor; Pyrido[2,3-d]pyrimidine phosphoinositide; Pyrido[3,2-d]pyrimidine; mTOR.

MeSH terms

Adenosine Triphosphate / chemistry
Adenosine Triphosphate / metabolism
Antineoplastic Agents / chemical synthesis*
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology
Binding Sites
Binding, Competitive
Cell Line, Tumor
Cell Survival / drug effects
Class I Phosphatidylinositol 3-Kinases
Drug Design*
Humans
Inhibitory Concentration 50
MCF-7 Cells
Molecular Docking Simulation
Phosphatidylinositol 3-Kinases / metabolism
Phosphoinositide-3 Kinase Inhibitors*
Protein Structure, Tertiary
Pyrimidines / chemical synthesis
Pyrimidines / chemistry*
Pyrimidines / pharmacology
Structure-Activity Relationship
TOR Serine-Threonine Kinases / antagonists & inhibitors*
TOR Serine-Threonine Kinases / metabolism

Substances

Antineoplastic Agents
Phosphoinositide-3 Kinase Inhibitors
Pyrimidines
Adenosine Triphosphate
Class I Phosphatidylinositol 3-Kinases
PIK3CA protein, human
TOR Serine-Threonine Kinases