title: Combined PI3K and CDK2 inhibition induces cell death and enhances in vivo antitumour activity in colorectal cancer.
abstract: The phosphatidylinositol-3-kinase/mammalian target of rapamycin (PI3K/mTOR) pathway is commonly deregulated in human cancer, hence many PI3K and mTOR inhibitors have been developed and have now reached clinical trials. Similarly, CDKs have been investigated as cancer drug targets.
  
  
  
  We have synthesised and characterised a series of 6-aminopyrimidines identified from a kinase screen that inhibit PI3K and/or mTOR and/or CDK2. Kinase inhibition, tumour cell growth, cell cycle distribution, cytotoxicity and signalling experiments were undertaken in HCT116 and HT29 colorectal cancer cell lines, and in vivo HT29 efficacy studies.
  
  
  
  2,6-Diaminopyrimidines with an O(4)-cyclohexylmethyl substituent and a C-5-nitroso or cyano group (1,2,5) induced cell cycle phase alterations and were growth inhibitory (GI50<20 μM). Compound 1, but not 2 or 5, potently inhibits CDK2 (IC50=0.1 nM) as well as PI3K, and was cytotoxic at growth inhibitory concentrations. Consistent with kinase inhibition data, compound 1 reduced phospho-Rb and phospho-rS6 at GI50 concentrations. Combination of NU6102 (CDK2 inhibitor) and pictilisib (GDC-0941; pan-PI3K inhibitor) resulted in synergistic growth inhibition, and enhanced cytotoxicity in HT29 cells in vitro and HT29 tumour growth inhibition in vivo.
  
  
  
  These studies identified a novel series of mixed CDK2/PI3K inhibitors and demonstrate that dual targeting of CDK2 and PI3K can result in enhanced antitumour activity.
authors.affiliation: Newcastle Cancer Centre, Northern Institute for Cancer Research, Paul O'Gorman Building, Medical School, Newcastle University, Framlington Place, Newcastle-upon-Tyne NE2 4HH, UK.
authors.forename: Gary
authors.initials: G
authors.lastname: Beale
authors.affiliation: Newcastle Cancer Centre, Northern Institute for Cancer Research, Paul O'Gorman Building, Medical School, Newcastle University, Framlington Place, Newcastle-upon-Tyne NE2 4HH, UK.
authors.forename: Emma J
authors.initials: EJ
authors.lastname: Haagensen
authors.affiliation: Newcastle Cancer Centre, Northern Institute for Cancer Research, Paul O'Gorman Building, Medical School, Newcastle University, Framlington Place, Newcastle-upon-Tyne NE2 4HH, UK.
authors.forename: Huw D
authors.initials: HD
authors.lastname: Thomas
authors.affiliation: Newcastle Cancer Centre, Northern Institute for Cancer Research, Paul O'Gorman Building, Medical School, Newcastle University, Framlington Place, Newcastle-upon-Tyne NE2 4HH, UK.
authors.forename: Lan-Zhen
authors.initials: LZ
authors.lastname: Wang
authors.affiliation: Newcastle Cancer Centre, Northern Institute for Cancer Research, School of Chemistry, Newcastle University, Bedson Building, Newcastle NE1 7RU, UK.
authors.forename: Charlotte H
authors.initials: CH
authors.lastname: Revill
authors.affiliation: Newcastle Cancer Centre, Northern Institute for Cancer Research, School of Chemistry, Newcastle University, Bedson Building, Newcastle NE1 7RU, UK.
authors.forename: Sara L
authors.initials: SL
authors.lastname: Payne
authors.affiliation: Newcastle Cancer Centre, Northern Institute for Cancer Research, School of Chemistry, Newcastle University, Bedson Building, Newcastle NE1 7RU, UK.
authors.forename: Bernard T
authors.initials: BT
authors.lastname: Golding
authors.affiliation: Newcastle Cancer Centre, Northern Institute for Cancer Research, School of Chemistry, Newcastle University, Bedson Building, Newcastle NE1 7RU, UK.
authors.forename: Ian R
authors.initials: IR
authors.lastname: Hardcastle
authors.affiliation: Newcastle Cancer Centre, Northern Institute for Cancer Research, Paul O'Gorman Building, Medical School, Newcastle University, Framlington Place, Newcastle-upon-Tyne NE2 4HH, UK.
authors.forename: David R
authors.initials: DR
authors.lastname: Newell
authors.affiliation: Newcastle Cancer Centre, Northern Institute for Cancer Research, School of Chemistry, Newcastle University, Bedson Building, Newcastle NE1 7RU, UK.
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Griffin
authors.affiliation: Newcastle Cancer Centre, Northern Institute for Cancer Research, School of Chemistry, Newcastle University, Bedson Building, Newcastle NE1 7RU, UK.
authors.forename: Celine
authors.initials: C
authors.lastname: Cano
mesh_terms: D000230:Adenocarcinoma / Q000201:enzymology / Q000473:pathology*; D000818:Animals; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000201:enzymology / Q000473:pathology*; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors* / Q000502:physiology; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000502:physiology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use*; D011897:Random Allocation; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D014410:Tumor Stem Cell Assay; D023041:Xenograft Model Antitumor Assays
chemical_list: D051357:Cyclin-Dependent Kinase 2; D009363:Neoplasm Proteins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D020033:Protein Isoforms; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human; C495894:CDK2 protein, human