DeChristopher Brian A, Fan Alice C, Felsher Dean W, Wender Paul A
Departments of Chemistry and Chemical and Systems Biology, Stanford University, Stanford, CA 94305-5080.
Oncotarget. 2012 Jan;3(1):58-66. doi: 10.18632/oncotarget.438.
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.
苔藓抑素1是一种天然存在的具有强大抗肿瘤活性的复杂大环内酯类化合物。然而，其极低的天然产量阻碍了临床进展。我们开发了一种策略，旨在设计更简化且合成上更容易获得的苔藓抑素类似物。我们的先导类似物“picolog”可以通过逐步经济的方式生产。与苔藓抑素相比，picolog在体外对MYC诱导的淋巴瘤表现出更强的生长抑制作用。picolog（以及苔藓抑素）活性的关键机制是蛋白激酶C（PKC）的激活。一种新型纳米免疫分析（NIA）显示，picolog处理可增加PKC途径中的磷酸化MEK2。此外，PKC的抑制消除了picolog的活性。最后，picolog在100微克/千克时具有高效力，并且在体内以100微克/千克至1毫克/千克的剂量治疗我们的MYC诱导淋巴瘤侵袭性模型时耐受性良好。我们首次在体内验证了苔藓抑素类似物picolog是一种治疗癌症和其他疾病的潜在治疗剂。
