Significant antitumor activity in vivo following treatment with the microtubule agent ENMD-1198.
Clinical studies using the microtubule-targeting agent 2-methoxyestradiol (2ME2; Panzem) in cancer patients show that treatment is associated with clinical benefit, including prolonged stable disease, complete and partial responses, and an excellent safety profile. Studies have shown that 2ME2 is metabolized by conjugation at positions 3 and 17 and oxidation at position 17. To define structure-activity relationships for these positions of 2ME2 and to generate metabolically stable analogues with improved anti-tubulin properties, a series of analogues was generated and three lead analogues were selected, ENMD-1198, ENMD-1200, and ENMD-1237. These molecules showed improved metabolic stability with >65% remaining after 2-h incubation with hepatocytes. Pharmacokinetic studies showed that oral administration of the compounds resulted in increased plasma levels compared with 2ME2. All three analogues bind the colchicine binding site of tubulin, induce G(2)-M cell cycle arrest and apoptosis, and reduce hypoxia-inducible factor-1alpha levels. ENMD-1198 and ENMD-1200 showed improved in vitro antiproliferative activities. Significant reductions in tumor volumes compared with vehicle-treated mice were observed in an orthotopic breast carcinoma (MDA-MB-231) xenograft model following daily oral treatment with all compounds (ANOVA, P < 0.05). Significantly improved median survival time was observed with ENMD-1198 and ENMD-1237 (200 mg/kg/d) in a Lewis lung carcinoma metastatic model (P < 0.05). In both tumor models, the high-dose group of ENMD-1198 showed antitumor activity equivalent to that of cyclophosphamide. ENMD-1198 was selected as the lead molecule in this analogue series and is currently in a phase I clinical trial in patients with refractory solid tumors.
LaVallee
Theresa M
TM
EntreMed, Inc., 9640 Medical Center Drive, Rockville, MD 20850, USA.
Burke
Patricia A
PA
Swartz
Glenn M
GM
Hamel
Ernest
E
Agoston
Gregory E
GE
Shah
Jamshed
J
Suwandi
Lita
L
Hanson
Art D
AD
Fogler
William E
WE
Sidor
Carolyn F
CF
Treston
Anthony M
AM
D000077584:2-Methoxyestradiol; D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001667:Binding, Competitive / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003078:Colchicine / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D004958:Estradiol / Q000031:analogs & derivatives / Q000737:chemistry; D004963:Estrenes / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D016195:G2 Phase / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D020128:Inhibitory Concentration 50; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008870:Microtubules / Q000187:drug effects*; D008938:Mitosis / Q000187:drug effects; D051381:Rats; D016019:Survival Analysis; D014404:Tubulin / Q000378:metabolism; D050257:Tubulin Modulators / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*
C530263:2-methoxyoestra-1,3,5(10),16-tetraene-3-carboxamide; D000970:Antineoplastic Agents; D004963:Estrenes; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D014404:Tubulin; D050257:Tubulin Modulators; D004958:Estradiol; D000077584:2-Methoxyestradiol; D003078:Colchicine