Biomedical subjects

Robert T Lum

Publications and source records attributed to Robert T Lum.

4 recordsLinked to original sources

PubMed2005

Target-related affinity profiling: Telik's lead discovery technology.

Target-Related Affinity Profiling (TRAP) is a computational drug discovery technology that is based on 'affinity fingerprints', which are molecular descriptors derived from the protein binding preferences of small molecules. The underlying concepts of TRAP are reviewed. Affinity fingerprints are compared to molecular descriptors derived from chemical structures and shown to be a useful alternative for lead discovery. The TRAP screening process is described and two example applications are presented: I. the discovery of novel inhibitors of human intestinal carboxylesterase, and II. the discovery of novel inhibitors of cyclooxygenase-1 through the use of the affinity fingerprints of known cyclooxygenase-1 inhibitors. A summary of the complementary advantages of TRAP screening technology compared to traditional approaches to drug lead discovery concludes the review.

Animals↗

PubMed2004

Novel cyclooxygenase-1 inhibitors discovered using affinity fingerprints.

We used protein affinity fingerprints to discover structurally novel inhibitors of cyclooxygenase-1 (COX-1) by screening a selected number of compounds, thus providing an alternative to extensive screening. From the affinity fingerprints of 19 known COX-1 inhibitors, a computational model for COX-1 inhibition was constructed and used to select candidate inhibitors from our compound library to be tested in the COX-1 assay. Subsequent refinement of the model by including affinity fingerprints of inactive compounds identified three molecules that were more potent than ibuprofen, a commonly used COX-1 inhibitor. These compounds are structurally distinct from those used to build the model and were discovered by testing only 62 library compounds. The discovery of these leads demonstrates the efficiency with which affinity fingerprints can identify novel bioactive chemotypes from known drugs.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed2004

In vitro and in vivo prevention of HIV protease inhibitor-induced insulin resistance by a novel small molecule insulin receptor activator.

Protease inhibitor (PI) therapy for the treatment of patients infected with human immunodeficiency virus is frequently associated with insulin resistance and diabetic complications. These adverse effects of PI treatment result to a large extent from their inhibition of insulin-stimulated glucose transport. Insulin receptor (IR) activators that enhance the insulin signaling pathway could be effective in treating this resistance. However, there are no agents reported that reverse inhibition of insulin action by PIs. Herein, we describe the effects of TLK19781. This compound is a non-peptide, small molecule, activator of the IR. We now report in cultured cells, made insulin resistant HIV by PI treatment, that TLK19781 both increased the content of insulin-stimulated GLUT4 at the plasma membrane, and enhanced insulin-stimulated glucose transport. In addition, oral administration of TLK19781 with the PI, indinavir improved glucose tolerance in rats made insulin resistant. These results suggest, therefore, that IR activators such as TLK19781 may be useful in treating the insulin resistance associated with PIs.

3T3-L1 Cells↗

PubMed2003

Phase I study of TLK286 (glutathione S-transferase P1-1 activated glutathione analogue) in advanced refractory solid malignancies.

PURPOSE: The purpose of this study was to determine the dose-limiting toxicities (DLTs), the maximum tolerated dose, and the pharmacokinetics of the novel glutathione analog TLK286 administered by i.v. infusion. EXPERIMENTAL DESIGN: Patients with advanced malignancies received i.v. TLK286 administered as a 30-min constant rate infusion once every 3 weeks in escalating doses from 60 to 1280 mg/m(2). Patients underwent tumor assessment on day 43 and continued on treatment until disease progression or unacceptable toxicity. RESULTS: A total of 35 patients were treated with 109 cycles of TLK286. At 1280 mg/m(2), 3 of 5 patients developed one of two observed dose limiting toxicities (DLTs). The DLTs were: mild pancreatitis (1 of 5) and bladder symptoms (2 of 5) consisting of hematuria, dysuria, and urinary frequency. All of the patients with DLTs continued on TLK286 treatment at 960 mg/m(2) (one dose below maximum tolerated dose) without recurrence of DLTs. DLTs were transient, resolved without sequelae, and noncumulative. TLK286-related toxicities included grade 1-2 nausea, vomiting, fatigue, transient microscopic hematuria, and anemia. Of 31 evaluable patients, 10 patients continued therapy (median six cycles; range, four to nine cycles). Pharmacokinetic studies of TLK286 on cycle 1 revealed a mean elimination half-life of 18 min (95% confidence interval, 16.1-19.9). Dose-proportional increases in both maximum blood concentrations and area under the blood-concentration-time curve were observed over the dose range of 60-960 mg/m(2). CONCLUSION: TLK286 was well tolerated in this study. TLK286 safety and pharmacokinetics support disease-specific evaluations of TLK286 at doses <1280 mg/m(2) administered once every three weeks in the treatment of patients with advanced malignancies.

Adult↗