Development of novel PP2A activators for use in the treatment of acute myeloid leukaemia.
AAL(S), the chiral deoxy analog of the FDA approved drug FTY720, has been shown to inhibit proliferation and apoptosis in several cancer cell lines. It has been suggested that it does this by activating protein phosphatase 2A (PP2A). Here we report the synthesis of new cytotoxic analogs of AAL(S) and the evaluation of their cytotoxicity in two myeloid cell lines, one of which is sensitive to PP2A activation. We show that these analogs activate PP2A in these cells supporting the suggested mechanism for their cytotoxic properties. Our findings identify key structural motifs required for anti-cancer effects.
School of Chemistry, UNSW Australia, Sydney, NSW 2052, Australia. jonathan.morris@unsw.edu.au.
Hamish D
HD
Toop
School of Biomedical Sciences and Pharmacy, The University of Newcastle, Callaghan, NSW 2308, Australia and Hunter Medical Research Institute, Newcastle, NSW 2305, Australia.
Matthew D
MD
Dun
Calvary Mater Hospital, Newcastle, NSW 2298, Australia.
Bryony K
BK
Ross
School of Biomedical Sciences and Pharmacy, The University of Newcastle, Callaghan, NSW 2308, Australia and Hunter Medical Research Institute, Newcastle, NSW 2305, Australia.
Hayley M
HM
Flanagan
School of Biomedical Sciences and Pharmacy, The University of Newcastle, Callaghan, NSW 2308, Australia and Hunter Medical Research Institute, Newcastle, NSW 2305, Australia.
Nicole M
NM
Verrills
School of Chemistry, UNSW Australia, Sydney, NSW 2052, Australia. jonathan.morris@unsw.edu.au.
Jonathan C
JC
Morris
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D015195:Drug Design; D004789:Enzyme Activation / Q000187:drug effects; D000068876:Fingolimod Hydrochloride / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000201:enzymology; D054648:Protein Phosphatase 2 / Q000378:metabolism*
D000970:Antineoplastic Agents; D054648:Protein Phosphatase 2; D000068876:Fingolimod Hydrochloride