"Picolog," a synthetically-available bryostatin analog, inhibits growth of MYC-induced lymphoma in vivo.
Bryostatin 1 is a naturally occurring complex macrolide with potent anti-neoplastic activity. However, its extremely low natural occurrence has impeded clinical advancement. We developed a strategy directed at the design of simplified and synthetically more accessible bryostatin analogs. Our lead analog, "picolog", can be step-economically produced. Picolog, compared to bryostatin, exhibited superior growth inhibition of MYC-induced lymphoma in vitro. A key mechanism of picolog's (and bryostatin's) activity is activation of PKC. A novel nano-immunoassay (NIA) revealed that picolog treatment increased phospho-MEK2 in the PKC pathway.  Moreover, the inhibition of PKC abrogated picolog's activity. Finally, picolog was highly potent at 100 micrograms/kg and well tolerated at doses ranging from 100 micrograms/kg to 1 milligram/kg in vivo for the treatment of our aggressive model of MYC-induced lymphoma. We provide the first in vivo validation that the bryostatin analog, picolog, is a potential therapeutic agent for the treatment of cancer and other diseases.
Departments of Chemistry and Chemical and Systems Biology, Stanford University, Stanford, CA 94305-5080.
Brian A
BA
DeChristopher
Alice C
AC
Fan
Dean W
DW
Felsher
Paul A
PA
Wender
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D054713:Bryostatins / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D048708:Cell Growth Processes / Q000187:drug effects*; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D016259:Genes, myc / Q000502:physiology*; D006801:Humans; D019169:Jurkat Cells; D008223:Lymphoma / Q000235:genetics* / Q000473:pathology*; D051379:Mice; D008954:Models, Biological; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D054713:Bryostatins; C572555:picolog