1.E6201 [(3S,4R,5Z,8S,9S,11E)-14-(ethylamino)-8, 9,16-trihydroxy-3,4-dimethyl-3,4,9,19-tetrahydro-1H-2-benzoxacyclotetradecine-1,7(8H)-dione], a novel kinase inhibitor of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK)-1 and MEK kinase-1: in vitro characterization of its anti-inflammatory and antihyperproliferative activities.
Goto M1, Chow J, Muramoto K, Chiba K, Yamamoto S, Fujita M, Obaishi H, Tai K, Mizui Y, Tanaka I, Young D, Yang H, Wang YJ, Shirota H, Gusovsky F. J Pharmacol Exp Ther. 2009 Nov;331(2):485-95. doi: 10.1124/jpet.109.156554. Epub 2009 Aug 14.
The goal of this study is to identify a novel inhibitor with anti-inflammatory and antiproliferative properties for the treatment of psoriasis. Compound f152A1 [(3S,5Z,8S,11E)-8,9,16-trihydroxy-14-methoxy-3-methyl-3,4,9,10-tetrahydro-1H-benzo[c]oxacyclotetradecine1,7(8H)-dione] was identified as the main active metabolite with strong inhibitory activity against tumor necrosis factor-alpha (TNFalpha) transcription in a fraction originated from the fermentation broth of the fungus Curvularia verruculosa. Although active in cell-based assays, f152A1 was unstable in plasma and liver microsome preparations, thus limiting its pharmaceutical utilization. To improve the metabolic properties of f152A1, a medicinal chemistry program was undertaken, resulting in the generation of over 400 analogs of f152A1. Eventually, E6201 [(3S,4R,5Z,8S,9S,11E)-14-(ethylamino)-8,9,16-trihydroxy-3,4-dimethyl-3,4,9,19-tetrahydro-1H-2-benzoxacyclotetradecine-1,7(8H)-dione] was identified as a promising analog in this series.
2.Pharmacokinetic characterization of a natural product-inspired novel MEK1 inhibitor E6201 in preclinical species.
Kumar V1, Schuck EL, Pelletier RD, Farah N, Condon KB, Ye M, Rowbottom C, King BM, Zhang ZY, Saxton PL, Wong YN. Cancer Chemother Pharmacol. 2012 Jan;69(1):229-37. doi: 10.1007/s00280-011-1687-8. Epub 2011 Jun 23.
PURPOSE: E6201 is a natural product-inspired novel inhibitor of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase-1 (MEK1) and other kinases and is currently under development as an anticancer (parenteral administration) and antipsoriasis agent (topical application). In vitro and in vivo preclinical studies were performed to characterize the pharmacokinetics of E6201. Allometric scaling was applied to predict human pharmacokinetics of E6201.
3.Discovery of anti-inflammatory clinical candidate E6201, inspired from resorcylic lactone LL-Z1640-2, III.
Shen Y1, Boivin R, Yoneda N, Du H, Schiller S, Matsushima T, Goto M, Shirota H, Gusovsky F, Lemelin C, Jiang Y, Zhang Z, Pelletier R, Ikemori-Kawada M, Kawakami Y, Inoue A, Schnaderbeck M, Wang Y. Bioorg Med Chem Lett. 2010 May 15;20(10):3155-7. doi: 10.1016/j.bmcl.2010.03.087. Epub 2010 Mar 30.
Inspired by natural product, LL-Z1640-2, clinical candidate, E6201 (22) was discovered in a medicinal chemistry effort through total synthesis. The modification on C14-position to N-alkyl substitution showed to be potent in vitro and orally active in vivo in anti-inflammatory assays.
4.Phase III, randomized study of gemcitabine and oxaliplatin versus gemcitabine (fixed-dose rate infusion) compared with gemcitabine (30-minute infusion) in patients with pancreatic carcinoma E6201: a trial of the Eastern Cooperative Oncology Group.
Poplin E1, Feng Y, Berlin J, Rothenberg ML, Hochster H, Mitchell E, Alberts S, O'Dwyer P, Haller D, Catalano P, Cella D, Benson AB 3rd. J Clin Oncol. 2009 Aug 10;27(23):3778-85. doi: 10.1200/JCO.2008.20.9007. Epub 2009 Jul 6.
PURPOSE: Single-agent gemcitabine (GEM) is standard treatment of metastatic pancreatic cancer. Fixed-dose rate (FDR) GEM and GEM plus oxaliplatin have shown promise in early clinical trials. E6201 was designed to compare overall survival (OS) of standard weekly GEM 1,000 mg/m(2)/30 minutes versus GEM FDR 1,500 mg/m(2)/150 minutes or GEM 1,000 mg/m(2)/100 minutes/day 1 plus oxaliplatin 100 mg/m(2)/day 2 every 14 days (GEMOX).