David J Matthews

Exelixis, Inc, San Francisco, California, United States

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Publications (7)29.59 Total impact

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    ABSTRACT: Activation of the PI3K pathway is a frequent occurrence in human tumors and is thought to promote, growth, survival and resistance to diverse therapies. Here we report pharmacological characterization of the pyridopyrimidinone derivative, XL765 (SAR245409), a potent and highly selective pan inhibitor of Class I PI3Ks (alpha, beta, gamma, and delta) with activity against mTOR. Broad kinase selectivity profiling of >130 protein kinases revealed that XL765 is highly selective for Class I PI3Ks and mTOR over other kinases. In cellular assays, XL765 inhibits the formation of PIP3 in the membrane, and inhibits phosphorylation of AKT, p70S6K and S6 phosphorylation in multiple tumor cell lines with different genetic alterations impacting the PI3K pathway. In a panel of tumor cell lines, XL765 inhibits proliferation with a wide range of potencies, with evidence of an impact of genotype on sensitivity. In mouse xenograft models, oral administration of XL765 results in dose-dependent inhibition of phosphorylation of AKT, p70S6K, and S6 with a duration of action of approximately 24 h. Repeat dose administration of XL765 results in significant tumor growth inhibition in multiple human xenograft models in nude mice that is associated with anti-proliferative, anti-angiogenic, and pro-apoptotic effects.
    Molecular Cancer Therapeutics 03/2014; · 5.60 Impact Factor
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    ABSTRACT: The 70-kDa ribosomal protein S6 kinase (p70S6K) is part of the PI3K/AKT/mTOR pathway and has been implicated in cancer. High throughput screening versus p70S6K led to the identification of aminopyrimidine 3a as active inhibitor. Lead optimization of 3a resulted in highly potent, selective, and orally bioavailable pyrazolopyrimidines. In this manuscript we report the structure-activity relationship of this series and pharmacokinetic, pharmacodynamic, and efficacy data of the lead compound 13c.
    Bioorganic & medicinal chemistry letters 03/2012; 22(6):2283-6. · 2.65 Impact Factor
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    ABSTRACT: Activation of the PI3K/Akt/mTOR kinase pathway is frequently associated with human cancer. Selective inhibition of p70S6Kinase, which is the last kinase in the PI3K pathway, is not sufficient for strong tumor growth inhibition and can lead to activation of upstream proteins including Akt through relief of a negative feedback loop. Targeting multiple sites in the PI3K pathway might be beneficial for optimal activity. In this manuscript we report the design of dual Akt/p70S6K inhibitors and the evaluation of the lead compound 11b in vivo, which was eventually advanced into clinical development.
    Bioorganic & medicinal chemistry letters 03/2012; 22(8):2693-7. · 2.65 Impact Factor
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    ABSTRACT: A series of subtype selective sphingosine 1-phosphate receptor 1 (S1P(1)) antagonists are disclosed. Our high-throughput screening campaign revealed hit 1 for which an increase in potency and mouse oral exposure was achieved with minor modifications to the chemical scaffold. In vivo efficacy revealed that at high doses compounds 12 and 15 inhibited tumor growth. Further optimization of our lead series led to the discovery of proline derivatives 37 (XL541) and 38 which had similar efficacy as our first generation analogues at significantly lower doses. Analogue 37 displayed excellent pharmacokinetics and oral exposure in multiple species.
    Journal of Medicinal Chemistry 01/2012; 55(3):1368-81. · 5.61 Impact Factor
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    ABSTRACT: Mutations associated with resistance to kinase inhibition are an important mechanism of intrinsic or acquired loss of clinical efficacy for kinase-targeted therapeutics. We report the prospective discovery of ErbB2 mutations that confer resistance to the small-molecule inhibitor lapatinib. We did in vitro screening using a randomly mutagenized ErbB2 expression library in Ba/F3 cells, which were dependent on ErbB2 activity for survival and growth. Lapatinib resistance screens identified mutations at 16 different ErbB2 amino acid residues, with 12 mutated amino acids mapping to the kinase domain. Mutations conferring the greatest lapatinib resistance cluster in the NH2-terminal kinase lobe and hinge region. Structural computer modeling studies suggest that lapatinib resistance is caused by multiple mechanisms; including direct steric interference and restriction of conformational flexibility (the inactive state required for lapatinib binding is energetically unfavorable). ErbB2 T798I imparts the strongest lapatinib resistance effect and is analogous to the epidermal growth factor receptor T790M, ABL T315I, and cKIT T670I gatekeeper mutations that are associated with clinical drug resistance. ErbB2 mutants associated with lapatinib resistance transformed NIH-3T3 cells, including L755S and T733I mutations known to occur in human breast and gastric carcinomas, supporting a direct mechanism for lapatinib resistance in ErbB2-driven human cancers. The epidermal growth factor receptor/ErbB2/vascular endothelial growth factor receptor inhibitor EXEL-7647 was found to inhibit almost all lapatinib resistance-associated mutations. Furthermore, no ErbB2 mutations were found to be associated with EXEL-7647 resistance and lapatinib sensitivity. Taken together, these data suggest potential target-based mechanisms of resistance to lapatinib and suggest that EXEL-7647 may be able to circumvent these effects.
    Clinical Cancer Research 05/2008; 14(8):2465-75. · 7.84 Impact Factor
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    ABSTRACT: Chk1 and Chk2 kinases are critically involved in modulating DNA damage checkpoints. In particular, Chk1, a key activator of the S-phase DNA damage response, may be involved in resistance to genotoxic therapies that target DNA synthesis. We studied the in vitro and in vivo effects of EXEL-9844 (XL844), a potent, orally available, and specific inhibitor of Chk1 and Chk2, in combination with gemcitabine. In clonogenic assays using multiple cell lines in vitro, EXEL-9844 had only minor effects as a single agent but substantially enhanced gemcitabine-induced cell killing. Correspondingly, in PANC-1 cells, EXEL-9844 increased gemcitabine-induced H2AX phosphorylation, blocked Cdc25A phosphorylation, and induced premature mitotic entry. In a PANC-1 xenograft model, EXEL-9844 significantly enhanced gemcitabine antitumor activity but had limited effect as a single agent. Together, these data show that cell cycle checkpoint inhibitors may have significant clinical utility in potentiating the activity of gemcitabine.
    Cell cycle (Georgetown, Tex.) 02/2007; 6(1):104-10. · 5.24 Impact Factor
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    ABSTRACT: Receptor tyrosine kinases (RTKs), like ErbB2, are key mediators of cell cycle regulation. Mutations in the kinase domain of ErbB2 have been detected in various tumors and the receptor is a therapeutic target for small molecule kinase inhibitors, such as the recently approved drug lapatinib (Tykerb®). However, a major drawback of cancer therapies with RTK inhibitors is the relapse of patients who develop secondary resistance to chronic treatment. Drug-resistance mutations have been reported in the clinic for several RTKs, but large-scale genotyping of tumors is impractical and cannot uncover the full spectrum of resistant variants. To identify prospective ErbB2 mutations conferring resistance to lapatinib, we used a sophisticated method1 involving random, target-specific saturation mutagenesis and in vitro screening of the mutants for drug resistance. The V659E oncogenic variant of ErbB2 cDNA was cloned into a retroviral vector and propagated inside repair-deficient bacteria. The randomly mutagenized plasmid DNA was used to generate retroviral particles that infected Ba/F3 cells, rendering them dependent of ErbB2 activity for survival and growth in the absence of IL-3. Lapatinib-resistant Ba/F3 clones were selected in soft-agar medium and DNA was isolated for sequencing of the entire intracellular domain of ErbB2. Seventeen point mutations, altering 16 amino acids, were identified repeatedly in 122 of the 125 lapatinib-resistant colonies recovered by multiple independent rounds of in vitro selection, indicating saturation of the screening. Mutations L755S and T733I have previously been reported in clinical samples, but not in the context of drug resistance. Mutations were most common in the ErbB2 kinase domain, including T798I which was found in 35 independent clones and is analogous to the gatekeeper mutation associated with clinical drug resistance of other RTKs. The resistance-conferring potential of the mutations was confirmed by site-directed mutagenesis of the original V659E ErbB2 cDNA construct and stable expression in Ba/F3 cells. Ten-point dose response cell viability assays and Western blot analyses determined highest lapatinib survival and ErbB2 phosphorylation IC50 values for the mutants isolated most frequently in the initial screens. The T798I mutation had the strongest resistance effect, with IC50 values consistent with ErbB2-independent lapatinib-induced toxicity. Computer-based structural modeling suggested that highly resistant mutations may act by direct steric interference of lapatinib binding to the inactive form of ErbB2 or by restricting conformational flexibility of the kinase. Our study describes the molecular mechanism of ErbB2 resistance to small molecule mediated kinase inhibition and provides a list of lapatinib-resistance mutations that may be therapeutically relevant. 1Azam M, Latek RR, Daley GQ. Mechanisms of autoinhibition and STI-571/imatinib resistance revealed by mutagenesis of BCR-ABL. Cell 2003; 112:831-843.
    10th European Regional International society for the study of xenobiotics Meeting;