Scott J Weir

The Scripps Research Institute, La Jolla, CA, United States

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Publications (6)37.08 Total impact

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    ABSTRACT: Gastrointestinal Stromal Tumor (GIST) is a rare and therefore often neglected disease. Introduction of the kinase inhibitor, imatinib mesylate (IM) radically improved the clinical response of patients with GIST; however, its effects are often short-lived, with GISTs demonstrating a median time to progression of approximately two years. Although many investigational drugs, approved first for other cancers, have been subsequently evaluated for the management of GIST, few have greatly impacted the overall survival of patients with advance disease. We employed a novel, focused, drug repurposing effort for GIST including IM-resistant GIST evaluating a large library of FDA-approved drugs regardless of current indication. As a result of the drug repurposing screen, we identified eight FDA-approved drugs including fludarabine phosphate (F-AMP) that showed synergy with and/or overcame resistance to IM. F-AMP induces DNA damage, annexin V and caspase 3/7 activities as the cytotoxic effects on GIST cells including IM-resistant GIST cells. F-AMP and IM combination treatment showed greater inhibition of GIST cell proliferation when compared to IM alone and F-AMP alone. Successful in vivo experiments confirmed the combination of IM with F-AMP enhanced the antitumor effects compared to IM alone. Our results identified F-AMP as a promising, repurposed drug therapy for the treatment of GISTs, with potential to be administered in combination with IM or for treatment of IM-refractory tumors.
    Molecular Cancer Therapeutics 08/2014; · 5.60 Impact Factor
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    ABSTRACT: Despite significant treatment advances over the past decade, metastatic gastrointestinal stromal tumor (GIST) remains largely incurable. Rare diseases, such as GIST, individually affect small groups of patients but collectively are estimated to affect 25-30 million people in the U.S. alone. Given the costs associated with the discovery, development and registration of new drugs, orphan diseases such as GIST are often not pursued by mainstream pharmaceutical companies. As a result, "drug repurposing" or "repositioning", has emerged as an alternative to the traditional drug development process. In this study we screened 796 FDA-approved drugs and found that two of these compounds, auranofin and fludarabine phosphate, effectively and selectively inhibited the proliferation of GISTs including imatinib-resistant cells. One of the most notable drug hits, auranofin (Ridaura®), an oral, gold-containing agent approved by the FDA in 1985 for the treatment of rheumatoid arthritis (RA), was found to inhibit thioredoxin reductase (TrxR) activity and induce reactive oxygen species (ROS) production, leading to dramatic inhibition of GIST cell growth and viability. Importantly, the anti-cancer activity associated with auranofin was independent of IM resistant status, but was closely related to the endogenous and inducible levels of ROS, therefore is prior to IM response. Coupled with the fact auranofin has an established safety profile in patients, these findings suggest for the first time that auranofin may have clinical benefit for GIST patients, particularly in those suffering from imatinib-resistant and recurrent forms of this disease.
    Molecular Cancer Therapeutics 05/2013; · 5.60 Impact Factor
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    ABSTRACT: A unique heterocyclic carbamate prodrug of seco-CBI-indole(2) that releases no residual byproduct is reported as a new member of a class of hydrolyzable prodrugs of the duocarmycin and CC-1065 family of natural products. The prodrug was designed to be activated by hydrolysis of a carbamate releasing the free drug without the cleavage release of a traceable extraneous group. Unlike prior carbamate prodrugs examined that are rapidly cleaved in vivo, the cyclic carbamate was found to be exceptionally stable to hydrolysis under both chemical and biological conditions providing a slow, sustained release of the exceptionally potent free drug. An in vivo evaluation of the prodrug found that its efficacy exceeded that of the parent drug, that its therapeutic window of efficacy versus toxicity is much larger than the parent drug, and that its slow free drug release permitted the safe and efficacious use of doses 150-fold higher than the parent compound.
    Journal of Medicinal Chemistry 05/2012; 55(12):5878-86. · 5.61 Impact Factor
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    ABSTRACT: Emerging evidence suggests that feeding a high-fat diet (HFD) to rodents affects the expression of genes involved in drug transport. However, gender-specific effects of HFD on drug transport are not known. The multidrug resistance-associated protein 2 (Mrp2, Abcc2) is a transporter highly expressed in the hepatocyte canalicular membrane and is important for biliary excretion of glutathione-conjugated chemicals. The current study showed that hepatic Mrp2 expression was reduced by HFD feeding only in female, but not male, C57BL/6J mice. In order to determine whether down-regulation of Mrp2 in female mice altered chemical disposition and toxicity, the biliary excretion and hepatotoxicity of the Mrp2 substrate, α-naphthylisothiocyanate (ANIT), were assessed in male and female mice fed control diet or HFD for 4weeks. ANIT-induced biliary injury is a commonly used model of experimental cholestasis and has been shown to be dependent upon Mrp2-mediated efflux of an ANIT glutathione conjugate that selectively injures biliary epithelial cells. Interestingly, HFD feeding significantly reduced early-phase biliary ANIT excretion in female mice and largely protected against ANIT-induced liver injury. In summary, the current study showed that, at least in mice, HFD feeding can differentially regulate Mrp2 expression and function and depending upon the chemical exposure may enhance or reduce susceptibility to toxicity. Taken together, these data provide a novel interaction between diet and gender in regulating hepatobiliary excretion and susceptibility to injury.
    Toxicology and Applied Pharmacology 04/2012; 261(2):189-95. · 3.98 Impact Factor
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    ABSTRACT: A series of N-acyl O-amino derivatives of seco-CBI-indole(2) are reported and examined as prototypical members of a unique class of reductively activated (cleaved) prodrugs of the duocarmycin and CC-1065 family of antitumor agents. These prodrugs were designed to be potentially preferentially activated in hypoxic tumor environments which carry an intrinsically higher concentration of "reducing" nucleophiles (e.g., thiols) capable of activating such derivatives by nucleophilic cleavage of a weak N-O bond. A remarkable range of stabilities and a resulting direct correlation with in vitro/in vivo biological potencies was observed for these prodrugs, even enlisting subtle variations in the electronic and steric environment around the weak N-O bond. An in vivo evaluation of several of the prodrugs demonstrates that some approach the potency and exceed the efficacy of the free drug itself (CBI-indole(2)), suggesting the prodrugs may offer an additional advantage related to a controlled or targeted release.
    Journal of Medicinal Chemistry 10/2010; 53(21):7731-8. · 5.61 Impact Factor
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    ABSTRACT: N-Acyl O-amino phenol derivatives of CBI-TMI and CBI-indole2 are reported as prototypical members of a new class of reductively activated prodrugs of the duocarmycin and CC-1065 class of antitumor agents. The expectation being that hypoxic tumor environments, with their higher reducing capacity, carry an intrinsic higher concentration of "reducing" nucleophiles (e.g., thiols) capable of activating such derivatives (tunable N-O bond cleavage) and increasing their sensitivity to the prodrug treatment. Preliminary studies indicate the prodrugs effectively release the free drug in functional cellular assays for cytotoxic activity approaching or matching the activity of the free drug, yet remain essentially stable and unreactive to in vitro DNA alkylation conditions (<0.1-0.01% free drug release) and pH 7.0 phosphate buffer, and exhibit a robust half-life in human plasma (t1/2 = 3 h). Characterization of a representative O-(acylamino) prodrug in vivo indicates that they approach the potency and exceed the efficacy of the free drug itself (CBI-indole2), indicating that not only is the free drug effectively released from the inactive prodrug but also that they offer additional advantages related to a controlled or targeted release in vivo.
    Journal of the American Chemical Society 12/2007; 129(49):15391-7. · 10.68 Impact Factor