Current Medicinal Chemistry - Volume 27, Issue 25, 2020

Background: The complement system usually helps protect against microbial infection, but it could also be involved in the onset of various diseases. Inhibition of complement component 5 (C5) with eculizumab has resulted in a significant reduction of hemolysis, reduction of thromboembolic events, and increased survival in patients with Paroxysmal Nocturnal Hemoglobinuria (PNH). However, eculizumab requires frequent intravenous infusions due to the abundance of C5 in plasma and some patients may still experience breakthrough hemolysis. This review introduces the recent body of knowledge on recycling technology and discusses the likely therapeutic benefits of SKY59, a novel recycling antibody, for PNH and complement-mediated disorders. Methods: By using recycling technology, we created a novel anti-C5 antibody, SKY59, capable of binding to C5 pH-dependently. Results: In cynomolgus monkeys, SKY59 robustly inhibited C5 and complement activity for significantly longer than a conventional antibody. SKY59 also showed an inhibitory effect on C5 variant p.Arg885His, whereas eculizumab does not suppress complement activity in patients with this type of mutation. Conclusion: SKY59 is a promising anti-C5 biologic agent that has significant advantages over current therapies such as long duration of action and efficacy against C5 variants.

Complement plays a vital role in our innate immune defense against invasive microorganisms. Excessive complement activation or insufficient control of activation on host cells, however, is associated with several chronic disorders. Essential to the activation and amplification of the Alternative Pathway (AP) of complement, Complement Factor D (CFD) is a specific serine protease that cleaves its unique substrate, Complement Factor B (CFB) in complex with an activated form of complement component 3 (C3), to generate the AP C3 convertases C3(H2O)Bb and C3bBb. These convertases comprise a central component in eliciting effector responses following AP activation, and they also enable a powerful amplification loop for both the Classical Pathway (CP) and Lectin Pathway (LP) of complement. Because CFD is not required for the activation of either the CP or LP, selective CFD inhibition presents a favorable therapeutic approach to modulating complement activity that leaves intact the effector functions following CP and LP activation and thus poses a lower risk of bacterial infection than other complement-directed approaches. This review provides an update on inhibitors of CFD, which have evolved from irreversible small molecules that demonstrate poor selectivity to reversible small molecules and monoclonal antibodies that demonstrate exceptional selectivity and potency. The reversible small-molecule inhibitor danicopan (ACH-4471) has emerged recently as a promising therapeutic candidate. An overview of its discovery, preclinical pharmacology, Phase 1 clinical studies in healthy volunteers, and Phase 2 clinical studies in Paroxysmal Nocturnal Hemoglobinuria (PNH) patients is presented.

Background: The discovery that short oligonucleotides, termed aptamers, can fold into three-dimensional structures that allow them to selectively bind and inhibit the activity of pathogenic proteins is now over 25 years old. The invention of the SELEX methodology heralded in an era in which such nucleic acid-based ligands could be generated against a wide variety of therapeutic targets. Results: A large number of aptamers have now been identified by combinatorial chemistry methods in the laboratory and moreover, an increasing number have been discovered in nature. The affinities and activities of such aptamers have often been compared to that of antibodies, yet only a few of these agents have made it into clinical studies compared to a large and increasing number of therapeutic antibodies. One therapeutic aptamer targeting VEGF has made it to market, while 3 others have advanced as far as phase III clinical trials. Conclusion: In this manuscript, we hope the reader appreciates that the success of aptamers becoming a class of drugs is less about nucleic acid biochemistry and more about target validation and overall drug chemistry.

Mycobacterium tuberculosis, responsible for Tuberculosis (TB), remains the leading cause of mortality among infectious diseases worldwide from a single infectious agent, with an estimated 1.7 million deaths in 2016. Biotin is an essential cofactor in M. tuberculosis that is required for lipid biosynthesis and gluconeogenesis. M. tuberculosis relies on de novo biotin biosynthesis to obtain this vital cofactor since it cannot scavenge sufficient biotin from a mammalian host. The biotin biosynthetic pathway in M. tuberculosis has been well studied and rigorously genetically validated providing a solid foundation for medicinal chemistry efforts. This review examines the mechanism and structure of the enzymes involved in biotin biosynthesis and ligation, summarizes the reported genetic validation studies of the pathway, and then analyzes the most promising inhibitors and natural products obtained from structure-based drug design and phenotypic screening.

Tumor cells and tumor-associated stromal cells such as immune, endothelial and mesenchimal cells create a Tumor Microenvironment (TME) which allows tumor cell promotion, growth and dissemination while dampening the anti-tumor immune response. Efficient anti-tumor interventions have to keep into consideration the complexity of the TME and take advantage of immunotherapy and chemotherapy combined approaches. Thus, the aim of tumor therapy is to directly hit tumor cells and reverse endothelial and immune cell anergy. Selective targeting of tumor vasculature using TNFα-associated peptides or antibody fragments in association with chemotherapeutic agents, has been shown to exert a potent stimulatory effect on endothelial cells as well as on innate and adaptive immune responses. These drug combinations reducing the dose of single agents employed have led to minimize the associated side effects. In this review, we will analyze different TNFα-mediated tumor vesseltargeted therapies in both humans and tumor mouse models, with emphasis on the role played by the cross-talk between natural killer and dendritic cells and on the ability of TNFα to trigger tumor vessel activation and normalization. The improvement of the TNFα-based therapy with anti-angiogenic immunomodulatory drugs that may convert the TME from immunosuppressive to immunostimulant, will be discussed as well.

The introduction of anti-EGFR (cetuximab and panitumumab) and antiangiogenic (bevacizumab, regorafeninb, ramucirumab, and aflibercept) agents in the therapeutic armamentarium of the metastatic Colorectal Cancer (CRC) has significantly improved the therapeutic efficacy and patients survival. However, despite the great improvements achieved in the patients life expectation, the high inter-individual heterogeneity in the response to the targeted agents still represent an issue for the management of advanced CRC patients. Even if the role of tumor genetic mutations as predictive markers of drug efficacy has been well-established, the contribution of the host genetic markers is still controversial. Promising results regard the germ-line immune-profile, inflammation and tumor microenvironment. Inherent variations in KRAS 3’UTR region as well as EGF/ EGFR genes were investigated as markers of cetuximab effectiveness. More recently interesting data in the field of anti- EGFR agents were generated also for germ-line variants in genes involved in inflammation (e.g. COX-2, LIFR, IGF1 signaling), immune system (e.g., FCGRs, IL-1RA), and other players of the RAS signaling, including the Hippo pathway related genes (e.g. Rassf, YAP, TAZ). Host genetic variants in VEGF-dependent (i.e., EGF, IGF-1, HIF1α, eNOS, iNOS) and -independent (i.e., EMT cascade, EGFL7) pathways, with specific attention on inflammation and immune system-related factors (e.g., IL-8, CXCR-1/2, CXCR4-CXCL12 axis, TLRs, GADD34, PPP1R15A, ANXA11, MKNK1), were investigated as predictive markers of bevacizumab outcome, generating some promising results. In this review, we aimed to summarize the most recent literature data regarding the potential role of common and rare inhered variants in predicting which CRC patients will benefit more from a specifically targeted drug administration.

Rectal cancer response to neoadjuvant Chemoradiotherapy (pCRT) is highly variable. In fact, it has been estimated that only about 21 % of patients show pathologic Complete Response (pCR) after therapy, while in most of the patients a partial or incomplete tumour regression is observed. Consequently, patients with a priori chemoradioresistant tumour should not receive the treatment, which is associated with substantial adverse effects and does not guarantee any clinical benefit. For Locally Advanced Rectal Cancer Patients (LARC), a standardized neoadjuvant treatment protocol is applied, the identification and the usefulness of prognostic or predictive biomarkers can improve the antitumoural treatment strategy, modifying the sequence, dose, and combination of radiotherapy, chemotherapy and surgical resection. For these reasons, a growing number of studies are actually focussed on the discovery and investigation of new predictive biomarkers of response to pCRT. In this review, we have selected the most recent literature (2012-2017) regarding the employment of blood-based biomarkers potentially predicting pCR in LARC patients and we have critically discussed them to highlight their real clinical benefit and the current limitations of the proposed methodological approaches.