Taxane analogues: distinguishing royal robes from the "Emperor's New Clothes".
Explore the source record for details and available documents.
ATP Binding Cassette Transporter, Subfamily B, Mem↗
Biomedical subjects
Eric K Rowinsky
Publications and source records attributed to Eric K Rowinsky.
Preclinical and clinical pharmacodynamic assessment of L-778,123, a dual inhibitor of farnesyl:protein transferase and geranylgeranyl:protein transferase type-I.
Farnesyl:protein transferase (FPTase) inhibitors were developed as anti-Ras drugs, but they fail to inhibit Ki-Ras activity because Ki-Ras can be modified by geranylgeranyl:protein transferase type-I (GGPTase-I). L-778,123, an inhibitor of FPTase and GGPTase-I, was developed in part because it can completely inhibit Ki-Ras prenylation. To support the clinical development of L-778,123, we developed pharmacodynamic assays using peripheral blood mononuclear cells (PBMCs) to measure the inhibition of prenylation of HDJ2 and Rap1A, proteins that are FPTase- and GGPTase-I substrates, respectively. We validated these assays in animal models and show that inhibition of HDJ2 prenylation in mouse PBMCs correlates with the concentration of FPTase inhibitors in blood. In dogs, continuous infusion of L-778,123 inhibited both HDJ2 and Rap1A prenylation in PBMCs, but we did not detect inhibition of Ki-Ras prenylation. We reported previously results from the first L-778,123 Phase I trial that showed a dose-dependent inhibition of HDJ2 farnesylation in PBMCs. In this report, we present additional analysis of patient samples from this trial and a second Phase I trial of L-778,123, and demonstrate the inhibition of both HDJ2 and Rap1A prenylation in PBMC samples. This study represents the first demonstration of GGPTase-I inhibition in humans. However, no inhibition of Ki-Ras prenylation by L-778,123 was detected in patient samples. These results confirm the pharmacologic profile of L-778,123 in humans as a dual inhibitor of FPTase and GGPTase-I, but indicate that the intended target of the drug, Ki-Ras, was not inhibited.
Alkyl and Aryl Transferases↗
Novel anticancer agents in clinical development.
There are currently more than 100 agents officially approved for the treatment of cancer world-wide. However, the most common epithelial cancers, which cause greater than 75% of cancer deaths, remain incurable. Most therapeutic agents have been developed empirically by testing large numbers of chemicals on rapidly growing transplantable rodent tumors, and more recently, human tumor xenografts. This approach has predominantly identified DNA-active drugs, which have limited efficacy and considerable toxicity. Novel agents, which selectively target aberrant elements in neoplastic cells and their microenvironment, are needed to improve the cure rates of epithelial malignancies. In recent years, advances in the understanding of molecular genetics and tumor biology have elucidated the molecular pathways implicated in the pathogenesis and progression of cancers and resulted in the discovery of a variety of novel molecular targets for therapeutic intervention. These targets can be conceptualized as supportive vessels, connective tissues, and signaling elements. Agents directed against these targets are those that interfere with signal transduction pathways, cell cycle regulation, and apoptosis (signals), malignant angiogenesis (vessels) and the tumor stroma (connective tissue). As anti-cancer therapeutics with distinct targeting capabilities against malignant cells become available for clinical evaluations, prioritization of these therapies for efficient allotment of clinical trial resources, identification of patients whose malignancies most likely express the molecular constituents resembling the true target, and derivation of relevant endpoints for both screening and assessment of clinical relevance will be critical to their ultimate development and success. This review will highlight promising rationally designed, target-based agents in clinical development, as well as the unique challenges involved in their successful development.
Animals↗
The molecular target of rapamycin (mTOR) as a therapeutic target against cancer.
The molecular target of rapamycin (mTOR), which is a member of the phosphoinositide 3-kinase related kinase (PIKK) family and a central modulator of cell growth, is a prime strategic target for anti-cancer therapeutic development. mTOR plays a critical role in transducing proliferative signals mediated through the phosphatidylinositol 3 kinase (PI3K)/protein kinase B (Akt) signaling pathway, principally by activating downstream protein kinases that are required for both ribosomal biosynthesis and translation of key mRNAs of proteins required for G(1) to S phase traverse. By targeting mTOR, the immunsuppressant and antiproliferative agent rapamycin (RAP) inhibits signals required for cell cycle progression, cell growth, and proliferation. RAP, a complex macrolide and highly potent fungicide, immunosuppressant, and anti-cancer agent, is a highly specific inhibitor of mTOR. In essence, RAP gains function by binding to the immunophilin FK506 binding protein 12 (FKBP12) and the resultant complex inhibits the activity of mTOR. Since mTOR activates both the 40S ribosomal protein S6 kinase ((p)70(s6k)) and the eukaryotic initiation factor 4E-binding protein-1 (4E-BP1), RAP blocks activation of these downstream signaling elements, which results in cell cycle arrest in the G1 arrest. RAP also prevents cyclin-dependent kinase (cdk) activation, inhibits retinoblastoma protein ((p)Rb) phosphorylation, and accelerates the turnover of cyclin D1 that leads to a deficienciy of active cdk4/cyclin D1 complexes, all of which potentially contribute to the prominent inhibitory effects of RAP at the G(1)/S phase transition. Both RAP and several RAP analogs with more favorable pharmaceutical properties have demonstrated prominent growth inhibitory effects against a broad range of human cancers in both preclinical and early clinical evaluations. This review will summarize the principal mechanisms of action of RAP and RAP derivatives and their potential utility of these agents as anti-cancer therapeutics. The preliminary results of early clinical evaluations with RAP analogs and the unique developmental challenges that lie ahead will also be discussed.
Adaptor Proteins, Signal Transducing↗