AbstractOur studies showed that Kevetrin™, a small molecule currently under development, has potent antitumor activity in several wild type and mutant p53 human tumor xenografts e.g. A549, PC-3, MDA-MB-231, HT-29, NCI-H1975, HCT-15, K-562, LNCaP. To investigate the mechanism of action of its antitumor activity in different xenograft models, we assessed Kevetrin's effects on apoptosis and cell cycle progression. Rb-E2F and MDM2-p53 pathways are crucial regulators of cell cycle progression. Remarkably, both Rb-E2F and MDM2-p53 pathways are defective in most, if not all, human tumors. There is extensive crosstalk between the Rb-E2F and MDM2-p53 pathways, especially between the transcription factors E2F1 and p53, which influence vital cellular decisions. In wild type p53 human lung carcinoma (A549), Kevetrin showed a concentration dependent increase in activation of p53 by Western blot analysis. Activated p53 triggered apoptosis by inducing the expression of PUMA. Kevetrin also increased the expression of the target gene p21, an inhibitor of cell cycle progression. Kevetrin induced apoptosis in a transcriptional independent way by altering the E3 ligase processivity of MDM2. Kevetrin strongly induced apoptosis in multiple tumor cell lines characterized by activation of caspase3 and PARP. E2F1 is a pivotal transcription factor that integrates signals from a variety of G1/S phase regulators and modulates diverse functions, such as DNA synthesis, mitosis, apoptosis and senescence. E2F1 overexpression, observed in most tumors, is associated with tumor growth. Cells which overexpress E2F1 proved to be immune to induction of senescence. A recent study showed that depletion of E2F1 hinders cell cycle progression and induces senescence. Kevetrin down regulated E2F1 expression in various p53 wild type and mutant cell lines. Kevetrin also down regulated the E2F1 target gene thymidylate synthase (TS) in various tumor cell lines. Several reports have shown E2F1 overexpression correlates with TS expression. Effective inhibition of TS by Kevetrin could play a crucial role in tackling the problem of resistance. Kevetrin acting through both major pathways of tumor suppression, Rb-E2F and MDM2-p53, has far reaching consequences. Due to the complexity of proapoptotic and antiapoptotic pathways with multiple players involved and redundant signaling networks, blocking only one antiapoptotic factor may not result in robust antitumor activity. However, Kevetrin acts via multiple targets to produce potent efficacy in various xenograft tumor models. We have also demonstrated that Kevetrin is non-genotoxic. DNA damaging drugs result in rapid phosphorylation of H2A.X at Ser 139 by PI3K-like kinases; however, Kevetrin did not induce phosphorylation of H2A.X. Since Kevetrin was well-tolerated in GLP safety pharmacology and toxicity studies, we have submitted an IND application for a Phase I clinical trial at Dana Farber / Harvard Cancer Center for 2012.Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2874. doi:1538-7445.AM2012-2874

2009-12-01·Cancer Research

Abstract C49: AKT inhibitor has potent antitumor activity in human lung cancer xenograft models

作者: Banu, Naheed ; Fadela, K. Chafai ; Hiran, Tej ; Menon, Krishna

AbstractLung cancer accounts for more than 215,000 new cases annually in the United States, and is the single largest cause of cancer death accounting for more than 130,000 deaths each year. Non-small cell lung cancer (NSCLC) accounts for 80% of all bronchogenic neoplasms with 90% of diagnosed patients dying within five years; therefore, new therapies are strongly desired. Effective therapies will come from a more detailed understanding of the molecular mechanisms underlying both the disease and the clinical response. We are developing a novel molecule, termed Kevetrin™, which was effective in reducing tumor growth in human lung cancer xenograft models while being well-tolerated. Kevetrin appeared to exert its anti-tumor activity by lowering levels of activated AKT also known as protein kinase B, of the AKT signal transduction pathway resulting in reduced tumor cell survival. Activated AKT was measured by a sandwich ELISA specific for phosphorylated AKT protein. Kevetrin was also evaluated for anti-tumor activity in vivo in the NCI-H1975 and A549 lung xenograft tumor models. Tumor-bearing nude mice were treated intravenously (IV) with either 200 mg/kg Kevetrin three times every other day or 22 mg/kg paclitaxel four times every other day. After Kevetrin was incubated with cells in vitro, phosphorylated AKT levels were reduced leading us to test for anti-tumor activity in vivo. Results with NCI-H1975 tumors showed that Kevetrin significantly delayed median tumor growth by 34 days (142%) in the first experiment and 28 days (156%) in a repeat experiment compared to controls, whereas the tumor growth delay (TGD) of paclitaxel was just 4 days (17%) and 14 days (78%), respectively. No weight loss occurred during treatment with Kevetrin. Results with A549 tumors showed that Kevetrin significantly delayed median tumor growth by 11 days (33%) in the first experiment and 30 days (111%) in a repeat experiment compared to controls, whereas the TGD of paclitaxel was just 0 days (0%) and 3 days (11%), respectively. In this study, Kevetrin resulted in <5% weight loss during treatment. These results showed that Kevetrin exerted potent anti-tumor activity against two human lung xenograft tumor models, NCI-H1975 and A549, at a dose and schedule that was well-tolerated as indicated by a small transient weight loss during treatment. NCI-H1975 have the T790M and L858R mutations in epidermal growth factor receptor (EGFR) and A549 have the K-ras mutation and overexpress STAT3 and Nrf2; these mutations are associated with resistance to standard chemotherapy. The reduction of activated AKT may be a mechanism by which Kevetrin overcame resistance and showed efficacy in these tumor models. These studies demonstrate that Kevetrin has promising potential for the treatment of lung carcinoma, particularly in cases where tumors have become resistant to standard chemotherapy.Citation Information: Cancer Res 2009;69(23 Suppl):C49.

Discovery and characterization of Kevetrin: A small molecule with potent anticancer activity

作者: Ram, Siya ; Chafai-Fadela, Karima ; Kumar, Ashok ; Menon, Krishna ; Holden, Sylvia ; Rogers, Samantha ; Hiran, Tejindervir S.

Many small mols. possess anti-cancer activity but frequently display high levels of toxicity.Kevetrin, a small mol. with broad spectrum anti-cancer activity in xenograft tumor models (lung, breast, colon, prostate, squamous cell, and leukemia), was well tolerated with low toxicity.Cytotoxicity assays revealed a relatively low potency in vitro and yet Kevetrin was efficacious against multi-drug resistant tumors.Kevetrin inhibits tumor growth by arresting cells in the G2/M stage of cell division together with increased apoptosis.Cell cycle arrest was associated with a change in levels of G2/M proteins (CDK1, cdc25B and WEE1) and cell death was promoted by pro-apoptotic signaling (p53, MDM2, p21 and PUMA) that together affect the metabolic pathways in cancer cells.This presentation will discuss the SAR, mechanism of action, anti-tumor activity, pre-clin. pharmacol., and safety profiles that led to the advancement of Kevetrin into Phase I clin. trials.

100 项与 Cellceutix Pharma, Inc. 相关的药物交易

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100 项与 Cellceutix Pharma, Inc. 相关的转化医学

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