Torrey Pines Institute for Molecular Studies

About: Torrey Pines Institute for Molecular Studies is a nonprofit organization based out in San Diego, California, United States. It is known for research contribution in the topics: T cell & Antigen. The organization has 2323 authors who have published 2217 publications receiving 112618 citations.

Discovery of a series of phosphonic acid-containing thiazoles and orally bioavailable diamide prodrugs that lower glucose in diabetic animals through inhibition of fructose-1,6-bisphosphatase.

Abstract: Oral delivery of previously disclosed purine and benzimidazole fructose-1,6-bisphosphatase (FBPase) inhibitors via prodrugs failed, which was likely due to their high molecular weight (>600). Therefore, a smaller scaffold was desired, and a series of phosphonic acid-containing thiazoles, which exhibited high potency against human liver FBPase (IC(50) of 10-30 nM) and high selectivity relative to other 5'-adenosinemonophosphate (AMP)-binding enzymes, were discovered using a structure-guided drug design approach. The initial lead compound (30j) produced profound glucose lowering in rodent models of type 2 diabetes mellitus (T2DM) after parenteral administration. Various phosphonate prodrugs were explored without success, until a novel phosphonic diamide prodrug approach was implemented, which delivered compound 30j with good oral bioavailability (OBAV) (22-47%). Extensive lead optimization of both the thiazole FBPase inhibitors and their prodrugs culminated in the discovery of compound 35n (MB06322) as the first oral FBPase inhibitor advancing to human clinical trials as a potential treatment for T2DM.

Natural products as DNA methyltransferase inhibitors: a computer-aided discovery approach.

Abstract: DNA methyltransferases (DNMTs) represent promising targets for the development of unique anticancer drugs. However, all DNMT inhibitors currently in clinical use are nonselective cytosine analogs with significant cytotoxic side-effects. Several natural products, covering diverse chemical classes, have indicated DNMT inhibitory activity, but these effects have yet to be systematically evaluated. In this study, we provide experimental data suggesting that two of the most prominent natural products associated with DNA methylation inhibition, (−)-epigallocathechin-3-gallate (EGCG) and curcumin, have little or no pharmacologically relevant inhibitory activity. We therefore conducted a virtual screen of a large database of natural products with a validated homology model of the catalytic domain of DNMT1. The virtual screening focused on a lead-like subset of the natural products docked with DNMT1, using three docking programs, following a multistep docking approach. Prior to docking, the lead-like subset was characterized in terms of chemical space coverage and scaffold content. Consensus hits with high predicted docking affinity for DNMT1 by all three docking programs were identified. One hit showed DNMT1 inhibitory activity in a previous study. The virtual screening hits were located within the biological-relevant chemical space of drugs, and represent potential unique DNMT inhibitors of natural origin. Validation of these virtual screening hits is warranted.

Synthesis and Biochemical Evaluation of Δ2-Isoxazoline Derivatives as DNA Methyltransferase 1 Inhibitors

Abstract: A series of Δ2-isoxazoline constrained analogues of procaine/procainamide (7a–k and 8a–k) were prepared and their inhibitory activity against DNA methyltransferase 1 (DNMT1) was tested. Among them, derivative 7b is far more potent in vitro (IC50 = 150 μM) than other non-nucleoside inhibitors and also exhibits a strong and dose-dependent antiproliferative effect against HCT116 human colon carcinoma cells. The binding mode of 7b with the enzyme was also investigated by means of a simple competition assay as well as of docking simulations conducted using the recently published crystallographic structure of human DNMT1. On the basis of the findings, we assessed that the mode of inhibition of 7b is consistent with a competition with the cofactor and propose it as a novel lead compound for the development of non-nucleoside DNMT inhibitors.

Comparative mapping of Andropogoneae: Saccharum L. (sugarcane) and its relation to sorghum and maize

Abstract: Comparative genetic maps of Papuan Saccharum officinarum L (2n = 80) and S robustum (2n = 80) were constructed by using single-dose DNA markers (SDMs) SDM-framework maps of S officinarum and S robustum were compared with genetic maps of sorghum and maize by way of anchor restriction fragment length polymorphism probes The resulting comparisons showed striking colinearity between the sorghum and Saccharum genomes There were no differences in marker order between S officinarum and sorghum Furthermore, there were no alterations in SDM order between S officinarum and S robustum The S officinarum and S robustum maps also were compared with the map of the polysomic octoploid S spontaneum ‘SES 208’ (2n = 64, x = 8), thus permitting relations to homology groups (“chromosomes”) of S spontaneum to be studied Investigation of transmission genetics in S officinarum and S robustum confirmed preliminary results that showed incomplete polysomy in these species Because of incomplete polysomy, multiple-dose markers could not be mapped for lack of a genetic model for their segregation To coalesce S officinarum and S robustum linkage groups into homology groups (composed of homologous pairing partners), they were compared with sorghum (2n = 20), which functioned as a synthetic diploid Groupings suggested by comparative mapping were found to be highly concordant with groupings based on highly polymorphic restriction fragment length polymorphism probes detecting multiple SDMs The resulting comparative maps serve as bridges to allow information from one Andropogoneae to be used by another, for breeding, ecology, evolution, and molecular biology