John K. Buolamwini

Cell Cycle Molecular Targets in Novel Anticancer Drug Discovery

A number of potential molecular targets for novel anticancer drug discovery have been identified in cell cycle control mechanisms. Prominent among these are the regulatory proteins, cyclins and their effector counterparts the cyclin dependent kinases (CDKs). Aberrant expression of these proteins, particularly cyclins involved in the G1 phase of the cell cycle, namely the D and E cyclins, has been associated with a variety of human cancers, including breast and colorectal cancer, B-lymphoma, prostate and non-small cell lung cancer. Inhibition of CDK kinase activity has turned out to be the most productive strategy for the discovery and design novel anticancer agents specifically targeting the cell cycle. Other potentially useful cell cycle areas for exploration include cyclin-CDK interactions, Cdc25 activation of cyclin-CDK complexes, ubiquitin-mediated proteolysis of cyclins, cell cycle check point kinases like Chk1, and recently identified oncogenic cell cycle-related aurora and polo-like kinases. Potent specific inhibitors have been identified that bind to the ATP site of CDKs, mainly cyclin B-CDK1, cyclin A-CDK2, and cyclin D-CDK4 complexes, and inhibit kinase activity. X-ray crystallographic data of CDKs, and their complexes with inhibitors have played a major role in the success of drug discovery efforts. Combinatorial chemistry, highthroughput screening, functional genomics and informatics have also contributed. CDK inhibitors currently under investigation include flavopiridol, olomoucine, roscovitine, puvalanol B, the dihydroindolo[3,2-d][1]benzazepinone kenpaullone, indirubin-3 -monoxime and novel diaminothiazoles such as AG12275. The anticancer therapeutic potential of CDK inhibitors has been demonstrated in preclinical studies, and Phases I and II clinical trials in cancer patients are currently underway.

Novel anticancer drug discovery.

There is at present, much optimism about the possibility of finding selective anticancer drugs that will eliminate the cytotoxic side effects associated with conventional cancer chemotherapy. This hope is based on uncovering many novel molecular targets that are cancer-specific, which will allow the targeting of cancer cells while normal cells are spared. Thus far, encouraging results have been obtained with several of these novel agents at the preclinical level, and clinical trials have begun. These targets are involved at one level or more in tumor biology, including tumor cell proliferation, angiogenesis and metastasis. Novel targets for which advances are being made include the following: growth factor receptor tyrosine kinases such as the epidermal growth factor receptor and HER-2/neu (proliferation); the vascular endothelial growth factor receptor and the basic fibroblast growth factor receptor (angiogenesis); the oncogenic GTP-binding protein Ras (especially agents targeting Ras farnesylation, farnesyltransferase inhibitors) (proliferation); protein kinase C (proliferation and drug resistance); cyclin-dependent kinases (proliferation); and matrix metalloproteinases and angiogenin (angiogenesis and metastasis). Less explored, but potentially useful targets include the receptor tyrosine kinase platelet-derived growth factor receptor, mitogen-activated protein kinase cascade oncogenes such as Raf-1 and mitogen-activated protein kinase kinase, cell adhesion molecules such as integrins, anti-apoptosis proteins such as Bcl-2, MDM2 and survivin, and the cell life-span target telomerase.

Application of the Electrotopological State Index to QSAR Analysis of Flavone Derivatives as HIV-1 Integrase Inhibitors

AbstractPurpose. A QSAR study based on electrotopological state (E-state) indices was conducted for a series of flavone HIV-1 integrase inhibitors to guide drug design.nMethods. E-state indices formulated to encode electronic and topological information for each skeletal atom in a molecule (Kier and Hall Pharm. Res. 7:801–807 (1990)) were calculated using the Molconn-X program, and partial least squares (PLS) multivariate regression was used to derive QSAR models.nResults. Predictive models with correlation coefficients (r2) of 0.98 (3 PLS components) and 0.99 (5 PLS components) and corresponding cross-validated correlation coefficients (c.v. r2) of 0.51 and 0.73, were obtained for inhibition of cleavage and integration, respectively, with one molecule omitted from the analysis.nConclusions. E-state indices at C6, C3′, C5′, C5, and O4 were found to be more important for prediction of activity than those for any of the other 12 flavone skeletal atoms that are common to the molecules in the data set.

Two novel cycloartane-type triterpene glycosides from the roots of Astragalus prusianus

Abstract Two novel cycloartane-type glycosides (1–2), 16-O-β- d -glucopyranosyl-20(S),24(R)-5(α),9-diepoxy-2α,3β,16β,25-tetrahydroxy-9,10-seco-cycloarta-1(10),6(7)-diene and 3-O-β- d -xylopyranosyl-16-O-β- d -glucopyranosyl-20(S),24(R)-epoxy-3β,16β,25-trihydroxycycloartane, were isolated from the roots of Astragalus prusianus. The 5α,9-epoxy structural feature in 1 is encountered for the first time.

Molecular targets in cancer drug discovery: cell-based profiling.

The phrase molecular target-based drug discovery usually implies an in vitro biochemical assay or battery of assays. One portion of the U.S. National Cancer Institutes drug discovery program, to the contrary, examines molecular targets for cancer therapy in a cell-based format. That approach has a number of significant limitations, but it has produced databases of significant utility on the activities and structures of tested compounds, as well as on molecular characteristics of the cell types used for testing.

Solution NMR Conformational Analysis of the Potent Equilibrative Sensitive (ES) Nucleoside Transporter Inhibitor, S 6-(4-Nitrobenzyl)mercaptopurine Riboside (NBMPR)

Abstract High resolution NMR analysis involving one-dimensional (1-D) 1H and nuclear Overhauser (NOE) difference spectroscopy was applied to solutions of NBMPR in DMSO-d 6. Coupling constants were obtained at different temperatures between 285 and 353 K, and used to analyze the rotamer preferences about the C-4′-C-5′ bond. The results revealed a rotamer distribution about the χ tortion angle that favors the high-anti range, a preponderance of the γ+ rotamer (at ∼64 %) with respect to the γ torsion angle, and a higher population of the south (S) conformer, which was favored by as little as the 4 % to as much as 31 % over the north (N) conformer as calculated by the program PSEUROT 6.2. The high-anti glycosidic torsion orientation appears to be the major conformational difference between the solution structure of NBMPR determined in this study and the structure previously observed in the solid state.