A Phase I/II Study Of NB1011 Administered Intravenously Daily For 5 Days Every 4 Weeks In Fluoropyrimidine-Resistant Metastatic Or Relapsed Colorectal Cancers

RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die.
PURPOSE: Phase I/II trial to study the effectiveness of NB1011 in treating patients who have metastatic or recurrent colorectal cancer that has not responded to previous treatment.

Start Date01 Dec 2001

Sponsor / Collaborator

NewBiotics, Inc.

100 Clinical Results associated with NewBiotics, Inc.

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01 Feb 2004·Antimicrobial Agents and ChemotherapyQ2 · MEDICINE

Mechanism of Action of NB2001 and NB2030, Novel Antibacterial Agents Activated by β-Lactamases

Q2 · MEDICINE

Article

Author: Bueno, Analia R. ; Li, Qing ; Stone, Geoffrey W. ; Castillo, Rosario ; Sergeeva, Maria ; Lee, Jean Y. ; Georgopapadakou, Nafsika H. ; Khambatta, Gody ; Zhang, Qin ; Doppalapudi, V. Ramana

ABSTRACT Two potent antibacterial agents designed to undergo enzyme-catalyzed therapeutic activation were evaluated for their mechanisms of action. The compounds, NB2001 and NB2030, contain a cephalosporin with a thienyl (NB2001) or a tetrazole (NB2030) ring at the C-7 position and are linked to the antibacterial triclosan at the C-3 position. The compounds exploit β-lactamases to release triclosan through hydrolysis of the β-lactam ring. Like cephalothin, NB2001 and NB2030 were hydrolyzed by class A β-lactamases ( Escherichia coli TEM-1 and, to a lesser degree, Staphylococcus aureus PC1) and class C β-lactamases ( Enterobacter cloacae P99 and E. coli AmpC) with comparable catalytic efficiencies ( kcat / K m ). They also bound to the penicillin-binding proteins of S. aureus and E. coli , but with reduced affinities relative to that of cephalothin. Accordingly, they produced a cell morphology in E. coli consistent with the toxophore rather than the β-lactam being responsible for antibacterial activity. In biochemical assays, they inhibited the triclosan target enoyl reductase (FabI), with 50% inhibitory concentrations being markedly reduced relative to that of free triclosan. The transport of NB2001, NB2030, and triclosan was rapid, with significant accumulation of triclosan in both S. aureus and E. coli . Taken together, the results suggest that NB2001 and NB2030 act primarily as triclosan prodrugs in S. aureus and E. coli .

01 Jul 2003·Anti-Cancer DrugsQ4 · MEDICINE

NB1011 induces Ser15 phosphorylation of p53 and activates the G2/M checkpoint

Q4 · MEDICINE

Article

Author: Karjian, Patricia L. ; Neuteboom, Saskia T. C. ; Dellinger, Ryan W.

NB1011, a phosphoramidate derivative of (E)-5-(2-bromovinyl)-2'-deoxyuridine, is a novel anti-cancer agent that selectively targets tumor cells expressing high levels of thymidylate synthase (TS), an enzyme required for DNA biosynthesis. NB1011 treatment of high-TS-expressing breast carcinoma cells (MCF7TDX) results in the induction of p53 and p21 protein levels, whereas no p53 or p21 induction is observed in the low-TS-expressing MCF7 tumor cells. Furthermore, MCF7TDX cells accumulate in the G(2)/M phase of the cell cycle in response to NB1011. In this study, the effect of NB1011 on the phosphorylation status of p53 was analyzed. We demonstrate that NB1011 treatment of various tumor cell lines expressing high TS results in the phosphorylation of p53 on Ser15, whereas this p53 phosphorylation is not observed in low-TS-expressing tumor cells. Also, we examined the role of several key cell cycle regulators in the growth inhibition observed in response to NB1011. Our results show that the mRNA and protein levels of the G(2)/M regulators cdc2, cyclin B1 and cdc25C are down-regulated in MCF7TDX cells, while unaffected in MCF7 cells. The mRNA and protein levels of 14-3-3sigma, also a direct transcriptional target of p53, are up-regulated in MCF7TDX cells following NB1011 treatment, while unchanged in MCF7 cells. Taken together, our data indicate that the growth inhibition caused by NB1011 in MCF7TDX cells is mediated through phosphorylation of p53 and activation of the G(2)/M checkpoint.

01 Aug 2002·Expert Opinion on Investigational DrugsQ2 · MEDICINE

Antifungals targeted to protein modification: focus on protein N-myristoyltransferase

Q2 · MEDICINE

Review

Author: Georgopapadakou, Nafsika H

Invasive fungal infections have increased dramatically in recent years to become important causes of morbidity and mortality in hospitalised patients. Currently available antifungal drugs for such infections essentially have three molecular targets: 14 alpha demethylase (azoles), ergosterol (polyenes) and beta-1,3-glucan synthase (echinocandins). The first is a fungistatic target vulnerable to resistance development; the second, while a fungicidal target, is not sufficiently different from the host to ensure high selectivity; the third, a fungistatic (Aspergillus) or fungicidal (Candida) target, has limited activity spectrum (gaps: Cryptococcus, emerging fungi) and potential host toxicity that might preclude dose escalation. Drugs aimed at totally new targets are thus needed to increase our chemotherapeutic options and to forestall, alone or in combination chemotherapy, the emergence of drug resistance. Protein N-myristoylation, the cotranslational transfer of the 14-carbon saturated fatty acid myristate from CoA to the amino-terminal glycine of several fungal proteins such as the ADP-ribosylation factor (ARF), presents such an attractive new target. The reaction, catalysed by myristoyl-CoA:protein N-myristoyltransferase (NMT), is essential for viability, is biochemically tractable and has proven potential for selectivity. In the past five years, a number of selective inhibitors of the fungal enzyme, some with potent, broad spectrum antifungal activity, have been reported: myristate analogues, myristoylpeptide derivatives, histidine analogues (peptidomimetics), aminobenzothiazoles, quinolines and benzofurans. A major development has been the publication of the crystal structure of Candida albicans and Saccharomyces cerevisiae NMTs, which has allowed virtual docking of inhibitors on the enzyme and refinement of structure-activity relationships of lead compounds.

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Drug(Targets)	Indications	Global Highest Phase

NB-301	Neoplasms More	Discontinued
NB-201	Neoplasms More	Discontinued
Thymectacin ( TYMS )	Colorectal Cancer More	Pending

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