Current Topics in Medicinal Chemistry - Volume 11, Issue 3, 2011

Protein-protein interactions are involved in the vast majority of biological processes that occur in living organisms from embryogenesis, cell-cell communication, receptor-ligand interactions, signal transduction pathways, gene transcription, metabolism, homeostasis and proliferation. Despite the potential importance of protein-protein interactions, researchers believed that finding small-molecule drugs to modulate PPIs would be nearly impossible, as protein-protein interfaces are generally large and devoid of well-defined cavities that can accommodate a small molecule, like those typically found on enzymes. Nonetheless, significant efforts in pharmaceutical and academic laboratories have been devoted to finding ways to exploit protein-protein interactions as drug targets. This issue of Current Topics in Medicinal Chemistry, dedicated to “The Protein- Protein Interactions as a Target in Medicinal Chemistry and Drug Discovery”, is aimed at describing the state of the art of current research and development in the field. The first review by Meireles and Mustata provides an overview of the principles underlying the main general strategies for discovering small-molecule modulators of protein-protein interactions, namely: high-throughput screening, fragment-based drug discovery, peptide-based drug discovery, protein secondary structure mimetics, and computer-aided drug discovery. The authors selected several examples of successful discovery of modulators of protein-protein interactions for each of these strategies. The cellular machineries that are involved in biological processes are complex assemblies of protein-protein and proteinoligonucleotide interactions. Any disruption of this interaction can lead to disease, including cancer. Garner and Janda examine the progress in the field of protein-protein interactions in cancer, their main focus being on small molecules, non-peptidic inhibitors at the transcription, mRNA splicing and transcription level. Understanding the molecular mechanisms of regulating apoptosis, or programmed cell death, is one of the hottest research areas in biomedical sciences. Apoptosis plays a major role in normal organism development, tissue homeostasis, and removal of damaged cells. Decreased or inhibited apoptosis is a hallmark of many malignancies and represents a major causative factor in the development and progression of cancer. Among others, the interaction of PUMA (p53 upregulated modulator of apoptosis)/Bcl-2 like proteins is a critical regulatory step in apoptosis initiation, particularly important in initiating radiationinduced apoptosis and damage in the gastrointestinal and hematopoietic systems. The research article contributed by investigators from the University of Pittsburgh (Mustata et al.) demonstrate that the synergism created by combining computational with experimental was key to the identification of small-molecule PUMA inhibitors for mitigating radiation induced cell death. Defective apoptosis can also be interrupted by a family of proteins termed inhibitors of apoptosis (IAP), which block apoptosis at the core of the apoptotic machinery by inhibiting effector caspases. The contribution by Straub provides an extensive examination of the progress in the development of IAPs, the chemical matter of the inhibitors and the biology emerging from the research in this field. Ballatore and colleagues highlight both progress and challenges associated with the use of MT-stabilizing agents and small molecule inhibitors of tau aggregation as potential treatments of Alzheimer's disease (AD) and related neurodegenerative diseases, collectively known as tauopathies. In the first part of the review, the authors summarize the current understanding of tau-mediated neurodegeneration as well as the rationale for therapeutic intervention based on MT-stabilizing agents and inhibitors of tau aggregation. Different classes of MT-stabilizing agents are reviewed with a particular emphasis on their potential to be developed as novel treatments for central nervous system (CNS) diseases like AD and related tauopathies. Finally, the authors discuss the “state-of-the-art” in the area of small molecule inhibitors of tau aggregation. Protein-protein interactions are clearly more challenging than other drug targets. Nevertheless, despite their challenging nature, significant progress has been made by researchers to discover modulators of protein-protein interactions. Notwithstanding the numerous examples included herein, this special issue is by no means comprehensive in its coverage. The significant progress that has been made by researchers demonstrates clearly that this target class holds considerable potential for new therapies and that the field will further develop in the coming years. We hope that you will find this special issue interesting and stimulating enough to bring your research endeavors in the area of protein-protein interactions to a higher level.

Protein-protein interactions are involved in most of the essential processes that occur in living organisms from cell motility to DNA replication, which makes them interesting targets for drug discovery. However, due to the lack of deep pockets, and the large contact surfaces involved in these interactions, they are considered challenging targets and have been often times dismissed as “undruggable”. Nonetheless, significant efforts in pharmaceutical and academic laboratories have been devoted to finding ways to exploit protein-protein interactions as drug targets. This article provides an overview of the principles underlying the main general strategies for discovering small-molecule modulators of protein-protein interactions, namely: high-throughput screening, fragment-based drug discovery, peptide-based drug discovery, protein secondary structure mimetics, and computer-aided drug discovery. In addition, examples of successful discovery of modulators of protein-protein interactions are discussed for each of those strategies.

Between 40,000 and 200,000 protein-protein interactions have been predicted to exist within the human interactome. As these interactions are of a critical nature in many important cellular functions and their dysregulation is causal of disease, the modulation of these binding events has emerged as a leading, yet difficult therapeutic arena. In particular, the targeting of protein-protein interactions relevant to cancer is of fundamental importance as the tumor-promoting function of several aberrantly expressed proteins in the cancerous state is directly resultant of its ability to interact with a protein- binding partner. Of significance, these protein complexes play a crucial role in each of the steps of the central dogma of molecular biology, the fundamental processes of genetic transmission. With the many important discoveries being made regarding the mechanisms of these genetic process, the identification of new chemical probes are needed to better understand and validate the druggability of protein-protein interactions related to the central dogma. In this review, we provide an overview of current small molecule-based protein-protein interaction inhibitors for each stage of the central dogma: transcription, mRNA splicing and translation. Importantly, through our analysis we have uncovered a lack of necessary probes targeting mRNA splicing and translation, thus, opening up the possibility for expansion of these fields.

PUMA (p53 upregulated modulator of apoptosis) is a Bcl-2 homology 3 (BH3)-only Bcl-2 family member and a key mediator of apoptosis induced by a wide variety of stimuli. PUMA is particularly important in initiating radiation induced apoptosis and damage in the gastrointestinal and hematopoietic systems. Unlike most BH3-only proteins, PUMA neutralizes all five known antiapoptotic Bcl-2 members through high affinity interactions with its BH3 domain to initiate mitochondria-dependent cell death. Using structural data on the conserved interactions of PUMA with Bcl-2-like proteins, we developed a pharmacophore model that mimics these interactions. In silico screening of the ZINC 8.0 database with this pharmacophore model yielded 142 compounds that could potentially disrupt these interactions. Thirteen structurally diverse compounds with favorable in silico ADME/Toxicity profiles have been retrieved from this set. Extensive testing of these compounds using cell-based and cell-free systems identified lead compounds that confer considerable protection against PUMA-dependent and radiation-induced apoptosis, and inhibit the interaction between PUMA and Bcl-xL.

Apoptosis is an essential process for embryonic and lymphocyte development, immune system modulation and tissue homeostasis. Defects in apoptotic signaling often lead to diseases of immune deficiency, neurodegeneration and cancer [1,2]. In the cancer arena, these defects may contribute to the establishment and growth of tumors. Moreover, many cytotoxic chemotherapies act in part by activating these apoptotic networks. Occasionally apoptotic pathways are activated, however key players downstream of initiation are inhibited by negative regulators that have been dysregulated by the diseased state of the cell. Removal of these barriers to apoptosis signaling, it has been rationalized, could restore cell death in diseased cells while sparing those that are not primed for programmed cell death. Additionally, the subversion of these death evading mechanisms may re-sensitize cells that have developed resistance to chemotherapies in this manner. The importance of apoptosis as a maintenance process, and the promise that restoring this signaling could mean in treating cancer has placed many targets on the front line of oncology research. Approaches are being developed that will activate death receptor pathways, synthetically activate caspases, restore the activity of tumor suppressor genes such as p53, and counteract the effects of anti-apoptotic factors. Among these approaches, small molecules are in clinical trials against several anti-apoptotic players, namely the Bcl-2 and IAP proteins. This review will focus on the efforts being advanced against the Inhibitor of Apoptosis Proteins (IAP), the chemical matter of the inhibitors and the biology emerging from this research.

The recognition that malfunction of the microtubule (MT) associated protein tau is likely to play a defining role in the onset and/or progression of a number of neurodegenerative diseases, including Alzheimer's disease, has resulted in the initiation of drug discovery programs that target this protein. Tau is an endogenous MT-stabilizing agent that is highly expressed in the axons of neurons. The MT-stabilizing function of tau is essential for the axonal transport of proteins, neurotransmitters and other cellular constituents. Under pathological conditions, tau misfolding and aggregation results in axonal transport deficits that appear to have deleterious consequences for the affected neurons, leading to synapse dysfunction and, ultimately, neuronal loss. This review focuses on both progress and unresolved issues surrounding the development of novel therapeutics for the treatment of neurodegenerative tauopathies, which are based on (A) MT-stabilizing agents to compensate for the loss of normal tau function and (B) small molecule inhibitors of tau aggregation.