Current Medicinal Chemistry - Volume 26, Issue 28, 2019

Introduction: Immunotherapy by using checkpoint inhibitors is now tried in the treatment of several malignancies, including Acute Myeloid Leukemia (AML). The treatment is tried both as monotherapy and as a part of combined therapy. Methods: Relevant publications were identified through literature searches in the PubMed database. We searched for (i) original articles describing the results from clinical studies of checkpoint inhibition; (ii) published articles describing the immunocompromised status of AML patients; and (iii) published studies of antileukemic immune reactivity and immunotherapy in AML. Results: Studies of monotherapy suggest that checkpoint inhibition has a modest antileukemic effect and complete hematological remissions are uncommon, whereas combination with conventional chemotherapy increases the antileukemic efficiency with acceptable toxicity. The experience with a combination of different checkpoint inhibitors is limited. Thalidomide derivatives are referred to as immunomodulatory drugs and seem to reverse leukemia-induced immunosuppression, but in addition, they have direct inhibitory effects on the AML cells. The combination of checkpoint targeting and thalidomide derivatives thus represents a strategy for dual immunotargeting together with a direct antileukemic effect. Conclusion: Checkpoint inhibitors are now tried in AML. Experimental studies suggest that these inhibitors should be combined with immunomodulatory agents (i.e. thalidomide derivatives) and/or new targeted or conventional antileukemic treatment. Such combinations would allow dual immunotargeting (checkpoint inhibitor, immunomodulatory agents) together with a double/triple direct targeting of the leukemic cells.

Background: Myeloid neoplasms are a diverse group of malignant diseases with different entities and numerous patho-clinical features. They arise from mutated clones of hematopoietic stem- and progenitor cells which expand by outperforming their normal counterparts. The intracellular signaling profile of cancer cells is the sum of genetic, epigenetic and microenvironmental influences, and the multiple interconnections between different signaling pathways make pharmacological targeting complicated. Objective: To present an overview of known somatic mutations in myeloproliferative neoplasms (MPN), myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) and the inflammatory signaling pathways affected by them, as well as current efforts to therapeutically modulate this aberrant inflammatory signaling. Methods: In this review, we extensively reviewed and compiled salient information with ClinicalTrials.gov as our source on ongoing studies, and PubMed as our authentic bibliographic source, using a focused review question. Results: Mutations affecting immune signal transduction are present to varying extents in clonal myeloid diseases. While MPN are dominated by a few common mutations, a multitude of different genes can be mutated in MDS and AML. Mutations can also occur in asymptomatic persons, a finding called clonal hematopoiesis of indeterminate potential (CHIP). Mutations in FLT3, JAK, STAT, CBL and RAS can lead to aberrant immune signaling. Protein kinase inhibitors are entering the clinic and are extensively investigated in clinical trials in MPN, MDS and AML. Conclusion: In summary, this article summarizes recent research on aberrant inflammatory signaling in clonal myeloid diseases and the clinical therapeutic potential of modulation of signal transduction and effector proteins in the affected pathways.

Acute Myeloid Leukaemia (AML) is the neoplastic transformation of Hematopoietic Stem Cells (HSC) and relapsed disease is a major challenge in the treatment. Despite technological advances in the field of medicine and our heightened knowledge regarding the pathogenesis of AML, the initial therapy of “7+3” Cytarabine and Daunorubicin has remained mainly unchanged since 1973. AML is a disease of the elderly, and increased morbidity in this patient group does not allow the full use of the treatment and drug-resistant relapse is common. Nanocarriers are drug-delivery systems that can be used to transport drugs to the bone marrow and target Leukemic Stem Cells (LSC), conferring less side-effects compared to the free-drug alternative. Nanocarriers also can be used to favour the transport of drugs that otherwise would not have been used clinically due to toxicity and poor efficacy. Liposomes are a type of nanocarrier that can be used as a dedicated drug delivery system, which can also have active ligands on the surface in order to interact with antigens on the target cells or tissues. In addition to using small molecules, it is possible to attach antibodies to the liposome surface, generating so-called immunoliposomes. By using immunoliposomes as a drug-delivery system, it is possible to minimize the toxic side effects caused by the chemotherapeutic drug on healthy organs, and at the same time direct the drugs towards the remaining AML blasts and stem cells. This article aims to explore the possibilities of using immunoliposomes as a drug carrier in AML therapy. Emphasis will be on possible target molecules on the AML cells, leukaemic stem cells, as well as bone marrow constituents relevant to AML therapy. Further, some conditions and precautions that must be met for immunoliposomes to be used in AML therapy will be discussed.

Background: Acute Myeloid Leukemia (AML) is a genetically heterogeneous disease characterized by uncontrolled proliferation of precursor myeloid-lineage cells in the bone marrow. AML is also characterized by patients with poor long-term survival outcomes due to relapse. Many efforts have been made to understand the biological heterogeneity of AML and the challenges to develop new therapies are therefore enormous. G Protein-coupled Receptors (GPCRs) are a large attractive drug-targeted family of transmembrane proteins, and aberrant GPCR expression and GPCR-mediated signaling have been implicated in leukemogenesis of AML. This review aims to identify the molecular players of GPCR signaling, focusing on the hematopoietic system, which are involved in AML to help developing novel drug targets and therapeutic strategies. Methods: We undertook an exhaustive and structured search of bibliographic databases for research focusing on GPCR, GPCR signaling and expression in AML. Results and Conclusion: Many scientific reports were found with compelling evidence for the involvement of aberrant GPCR expression and perturbed GPCR-mediated signaling in the development of AML. The comprehensive analysis of GPCR in AML provides potential clinical biomarkers for prognostication, disease monitoring and therapeutic guidance. It will also help to provide marker panels for monitoring in AML. We conclude that GPCR-mediated signaling is contributing to leukemogenesis of AML, and postulate that mass spectrometrybased protein profiling of primary AML cells will accelerate the discovery of potential GPCR related biomarkers for AML.

Background: Post-translational modification (PTM) crosstalk is a young research field. However, there is now evidence of the extraordinary characterization of the different proteoforms and their interactions in a biological environment that PTM crosstalk studies can describe. Besides gene expression and phosphorylation profiling of acute myeloid leukemia (AML) samples, the functional combination of several PTMs that might contribute to a better understanding of the complexity of the AML proteome remains to be discovered. Objective: By reviewing current workflows for the simultaneous enrichment of several PTMs and bioinformatics tools to analyze mass spectrometry (MS)-based data, our major objective is to introduce the PTM crosstalk field to the AML research community. Results: After an introduction to PTMs and PTM crosstalk, this review introduces several protocols for the simultaneous enrichment of PTMs. Two of them allow a simultaneous enrichment of at least three PTMs when using 0.5-2 mg of cell lysate. We have reviewed many of the bioinformatics tools used for PTM crosstalk discovery as its complex data analysis, mainly generated from MS, becomes challenging for most AML researchers. We have presented several non-AML PTM crosstalk studies throughout the review in order to show how important the characterization of PTM crosstalk becomes for the selection of disease biomarkers and therapeutic targets. Conclusion: Herein, we have reviewed the advances and pitfalls of the emerging PTM crosstalk field and its potential contribution to unravel the heterogeneity of AML. The complexity of sample preparation and bioinformatics workflows demands a good interaction between experts of several areas.

As a long-term degenerative disorder of the central nervous system that mostly affects older people, Parkinson’s disease is a growing health threat to our ever-aging population. Despite remarkable advances in our understanding of this disease, all therapeutics currently available only act to improve symptoms but cannot stop the disease progression. Therefore, it is essential that more effective drug discovery methods and approaches are developed, validated, and used for the discovery of disease-modifying treatments for Parkinson’s disease. Drug repurposing, also known as drug repositioning, or the process of finding new uses for existing or abandoned pharmaceuticals, has been recognized as a cost-effective and timeefficient way to develop new drugs, being equally promising as de novo drug discovery in the field of neurodegeneration and, more specifically for Parkinson’s disease. The availability of several established libraries of clinical drugs and fast evolvement in disease biology, genomics and bioinformatics has stimulated the momentums of both in silico and activity-based drug repurposing. With the successful clinical introduction of several repurposed drugs for Parkinson’s disease, drug repurposing has now become a robust alternative approach to the discovery and development of novel drugs for this disease. In this review, recent advances in drug repurposing for Parkinson’s disease will be discussed.

Drug repurposing is a safe and successful pathway to speed up the novel drug discovery and development processes compared with de novo drug discovery approaches. Drug repurposing uses FDA-approved drugs and drugs that failed in clinical trials, which have detailed information on potential toxicity, formulation, and pharmacology. Technical advancements in the informatics, genomics, and biological sciences account for the major success of drug repurposing in identifying secondary indications of existing drugs. Drug repurposing is playing a vital role in filling the gap in the discovery of potential antibiotics. Bacterial infections emerged as an ever-increasing global public health threat by dint of multidrug resistance to existing drugs. This raises the urgent need of development of new antibiotics that can effectively fight multidrug-resistant bacterial infections (MDRBIs). The present review describes the key role of drug repurposing in the development of antibiotics during 2016–2017 and of the details of recently FDA-approved antibiotics, pipeline antibiotics, and antibacterial properties of various FDA-approved drugs of anti-cancer, anti-fungal, anti-hyperlipidemia, antiinflammatory, anti-malarial, anti-parasitic, anti-viral, genetic disorder, immune modulator, etc. Further, in view of combination therapies with the existing antibiotics, their potential for new implications for MDRBIs is discussed. The current review may provide essential data for the development of quick, safe, effective, and novel antibiotics for current needs and suggest acuity in its effective implications for inhibiting MDRBIs by repurposing existing drugs.

Biomedical discovery has been reshaped upon the exploding digitization of data which can be retrieved from a number of sources, ranging from clinical pharmacology to cheminformatics-driven databases. Now, supercomputing platforms and publicly available resources such as biological, physicochemical, and clinical data, can all be integrated to construct a detailed map of signaling pathways and drug mechanisms of action in relation to drug candidates. Recent advancements in computer-aided data mining have facilitated analyses of ‘big data’ approaches and the discovery of new indications for pre-existing drugs has been accelerated. Linking gene-phenotype associations to predict novel drug-disease signatures or incorporating molecular structure information of drugs and protein targets with other kinds of data derived from systems biology provide great potential to accelerate drug discovery and improve the success of drug repurposing attempts. In this review, we highlight commonly used computational drug repurposing strategies, including bioinformatics and cheminformatics tools, to integrate large-scale data emerging from the systems biology, and consider both the challenges and opportunities of using this approach. Moreover, we provide successful examples and case studies that combined various in silico drug-repurposing strategies to predict potential novel uses for known therapeutics.

Background: Research into repositioning known drugs to treat cancer other than the originally intended disease continues to grow and develop, encouraged in part, by several recent success stories. Many of the studies in this article are geared towards repurposing generic drugs because additional clinical trials are relatively easy to perform and the drug safety profiles have previously been established. Objective: This review provides an overview of anticancer drug development strategies which is one of the important areas of drug restructuring. Methods: Repurposed drugs for cancer treatments are classified by their pharmacological effects. The successes and failures of important repurposed drugs as anticancer agents are evaluated in this review. Results and Conclusion: Drugs could have many off-target effects, and can be intelligently repurposed if the off-target effects can be employed for therapeutic purposes. In cancer, due to the heterogeneity of the disease, often targets are quite diverse, hence a number of already known drugs that interfere with these targets could be deployed or repurposed with appropriate research and development.