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ENMD-1198

Description of ENMD1198: ENMD-1198 is a potent, orally-active, antimitotic agent that induces cell cycle arrest and apoptosis in tumor cells. ENMD-1198 has shown pronounced antitumor activity as well as substantial synergistic effects in combination with standard of care chemotherapeutic agents in numerous preclinical models. ENMD-1198 does not exhibit sensitivity to multi-drug resistance mechanisms in preclinical studies. ENMD-1198 also has shown preclinical activity towards taxane and vinca alkaloid resistant tumor cells. Additionally, ENMD-1198 decreases the activity of three oncogenic proteins (HIF-1α, NF-κB and STAT3) that are known to promote tumor growth and progression. ENMD-1198 has been evaluated in a Phase 1 clinical trial for safety, tolerability, pharmacokinetics, and clinical benefit in advanced cancer patients. (source: http://www.entremed.com/science/enmd-1198/).

Current developer:  EntreMed, Inc.

ENMD-1198 is a new chemical entity (NCE) based on a modified chemical structure of 2ME2 designed to increase antitumor and antiangiogenic properties and improve metabolism. ENMD-1198 is characterized by its multiple mechanisms of action, which include inducing apoptosis, binding microtubules, and inhibiting HIF-1alpha. HIF-1alpha is over-expressed in more than 70% of human tumors and its over-expression correlates with tumor aggressiveness, metastases and poor prognosis. Preclinical studies identified ENMD-1198 as an orally active, microtubule disrupting agent that leads to arrest of cell division and apoptosis in tumor cells. Additionally, ENMD-1198 exerts antiangiogenic activity that contributes to its overall antitumor effects.

In preclinical studies, ENMD-1198 has demonstrated pronounced in vivo antitumor activity in models of human cancer. Oral daily treatment with ENMD- 1198 in an orthotopic MDA MB 231 breast cancer model led to a reduction in tumor burden equivalent to the positive control cyclophosphamide, disruption of microtubules within tumor cells, and a substantial decrease in HIF-1alpha. ENMD-1198 also reduced protein levels for two additional transcription factors, NFkB and Stat3, known to modulate HIF-1alpha protein levels in vitro. All three transcription factors are known to regulate multiple genes and their proteins that contribute to tumor growth and progression.

In preclinical tumor studies, serum proteins regulated by HIF-1alpha, NFkB and Stat3, were also reduced substantially following oral administration of ENMD-1198. Results from several studies demonstrate significantly (40-100%) decreased plasma or serum levels of human VEGF (secreted by tumor cells), a major proangiogenic growth factor, compared to control animals following therapy with ENMD-1198. Serum levels of human IL-6 were also decreased significantly (62-96%). Over-expression of IL-6 is associated with higher morbidity in breast cancers, bone metastases, increased aromatase synthesis, and increased cancer drug resistance. Tumor levels of a third tumor protein regulated by HIF-1alpha, carbonic anhydrase IX (CA IX), were also decreased, consistent with HIF-1alpha inhibition. (source: biospace.com)

1: Pasquier E, Sinnappan S, Munoz MA, Kavallaris M. ENMD-1198, a new analogue of 2-methoxyestradiol, displays both antiangiogenic and vascular-disrupting properties. Mol Cancer Ther. 2010 May;9(5):1408-18. Epub 2010 May 4. PubMed PMID: 20442304.

2: Zhou Q, Gustafson D, Nallapareddy S, Diab S, Leong S, Lewis K, Gore L, Messersmith WA, Treston AM, Eckhardt SG, Sidor C, Camidge DR. A phase I dose-escalation, safety and pharmacokinetic study of the 2-methoxyestradiol analog ENMD-1198 administered orally to patients with advanced cancer. Invest New Drugs. 2010 Jan 19. [Epub ahead of print] PubMed PMID: 20084425.

3: Agoston GE, Shah JH, Suwandi L, Hanson AD, Zhan X, LaVallee TM, Pribluda V, Treston AM. Synthesis, antiproliferative, and pharmacokinetic properties of 3- and 17-double-modified analogs of 2-methoxyestradiol. Bioorg Med Chem Lett. 2009 Nov 1;19(21):6241-4. Epub 2009 Aug 8. PubMed PMID: 19782564.

4: Moser C, Lang SA, Mori A, Hellerbrand C, Schlitt HJ, Geissler EK, Fogler WE, Stoeltzing O. ENMD-1198, a novel tubulin-binding agent reduces HIF-1alpha and STAT3 activity in human hepatocellular carcinoma(HCC) cells, and inhibits growth and vascularization in vivo. BMC Cancer. 2008 Jul 23;8:206. PubMed PMID: 18651980; PubMed Central PMCID: PMC2496914.

5: Foster PA, Stengel C, Ali T, Leese MP, Potter BV, Reed MJ, Purohit A, Newman SP. A comparison of two orally bioavailable anti-cancer agents, IRC-110160 and STX140. Anticancer Res. 2008 May-Jun;28(3A):1483-91. PubMed PMID: 18630502.

6: LaVallee TM, Burke PA, Swartz GM, Hamel E, Agoston GE, Shah J, Suwandi L, Hanson AD, Fogler WE, Sidor CF, Treston AM. Significant antitumor activity in vivo following treatment with the microtubule agent ENMD-1198. Mol Cancer Ther. 2008 Jun;7(6):1472-82. PubMed PMID: 18566218.