Abstract: Mainstays of therapy for type 2 diabetes involve drugs that are insulin-centric, i.e., they are designed to increase insulin secretion and decrease insulin resistance. The usual clinical course for people so treated is to have initially improved glycemic control but over time a need for intensification of drug-based treatment of hyperglycemia. The mechanism for this unrelenting deterioration of β-cell function is related to chronic oxidative stress. This suggests that drug discovery should not exclusively focus on insulin-centric targets, but also include glucose-centric strategies, such as antioxidant protection of the β-cell. This may facilitate repair of β-cells undergoing damage by oxidative stress secondary to chronic hyperglycemia. ... Read more

Abstract: Carbohydrates are ubiquitous and represent the most abundant class of molecules in nature. All cell surfaces are coated with complex carbohydrates where they act as recognition molecules for other cells, functional molecules, and pathogens. Consequently, they are involved in disease indications as diverse as inflammation, cancer, and infectious disease. In general, native carbohydrates lack the properties necessary for efficacious drugs and historically have not been successful candidates to capitalize on these applications. Understanding the bioactive conformation and molecular interactions of functional carbohydrates, however, allows the rational design of small molecule glycomimetics that exhibit improved drug-like properties such as increased affinity, serum half-life, stability, and bioavailability. Recent advances in analytical techniques (i.e., NMR, x-ray crystallization), molecular modeling, and synthetic organic chemistry allow the design of potent glycomimetic compounds, which opens the door to a new class of therapeutic drugs to target molecular mechanisms that can address many of the current unmet needs in the treatment of disease. ... Read more

Abstract: Drug combinations are an increasingly favored strategy for increasing therapeutic windows for potential drugs, but enthusiasm for this approach is tempered by concerns that therapeutic synergy will too often be mirrored by synergistic toxicity. Here we review our recent experimental results and numerical simulations that establish the context-specificity of synergistic combinations. Thus systematic testing of chemical combinations in cell-based disease models can preferentially discover synergies with beneficial therapeutic selectivity. For an anti-inflammatory combination, we demonstrate how such selective synergy is achieved through differential expression of its targets in cells associated with therapeutic and toxic effects, and validate the combination's therapeutic relevance in animals. The narrower context specificity of synergistic combinations creates many new opportunities for such therapeutically relevant selectivity, and reinforces the realization that the most useful paradigm for a drug target is often a set of biomolecules that cooperate to produce a therapeutic response with reduced side effects. ... Read more

Abstract: The loss of ability in controlling cell cycle leads to aberrant cell growth and is a hallmark of cancer cells. Cell cycle regulation and progression mainly rely on protein phosphorylation events, therefore cell cycle kinases have long been viewed as potential targets for anticancer strategies. Consistently, cell cycle kinases are often dysregulated in different types of human cancer. Despite years of research and attempts directed at inhibiting cell cycle kinases, none of these approaches has been successfully translated to the clinic to halt tumorigenesis. Here, we review several currently pursued strategies and highlight both current challenges and some recent findings, which might help to develop new, better conceived therapeutic approaches based on cell-cycle kinase inhibition. ... Read more

Abstract: It is estimated that 63% of drug targets are intracellular and cannot be reached by antibody drugs and many other therapeutic agents. Intrabody (single-chain antibody or its fragments) produced intracellularly is a promising technology that could bring forth intracellular therapeutics in addition to being an important research tool. ... Read more

Abstract: The 10+ year journey from benchtop to bedside is often a tumultuous one. For those researchers who successfully made it through this journey, the triumph is preceded by tenacity, perseverance, funding, good science, and sound strategy. They have "done right" on something that is critically important. Bortezomib (Velcade) for multiple myeloma represents a model paradigm that has a lot to teach us. ... Read more

Abstract: Chemistry has been the cornerstone in developing cancer drugs, from the conventional chemoagents to the target-specific ones such as the tyrosine kinase inhibitor Gleevec. In combination with forward and reverse genetic approaches and combinatorial screening technology, chemistry and a new breed of structural, molecular, and systems chemists are to play an even greater role in cancer drug discovery. ... Read more

Abstract: Comparisons of gene and protein profiling between sickness and health offer tremendous opportunities for finding new drug targets and aiding clinical trial design, in addition to fueling promising expansion of advanced diagnostics. ... Read more

Abstract: Advanced technologies such as high-throughput screening and combinatorial chemistry have taken the center stage in drug discovery, but they have yet to reach the the level scientists have expected. Though developing drugs from natural products is laborious and cumbersome, they boast ingenious molecular structures and have time and again proven to be important precursors to many effective drugs. ... Read more

Abstract: Have the big pharmaceutical companies stopped innovating? The answer is no. With pressure from both generic drug makers and peer competition, pharmaceutical companies, big and small, have every incentive to innovate. Experiencing a lull in recent years by big pharmaceutical companies, there is now the possibility of a sizable increase in new drug approvals over the coming years. ... Read more