Design, Synthesis, and Preclinical Characterization of Selective Factor D Inhibitors Targeting the Alternative Complement Pathway

Karki, Rajeshri G.; Powers, James J.; Mainolfi, Nello; Anderson, Karen; Belanger, David; Ji, Nan; Jendza, Keith; Gelin, Christine F.; Sweeney, A. Mac; Solovay, Catherine; Delgado, Omar; Crowley, Maura; Liao, Sha-Mei; Argikar, Upendra A.; Flohr, Stefanie; Bonte, Laura R. La; Lorthiois, Edwige; Vulpetti, Anna; Brown, Ann; Long, Debby; Prentiss, Melissa; Gradoux, Nathalie; Erkenez, A. De; Cumin, Frédéric; Adams, Christopher M.; Jaffee, Bruce; Mogi, Muneto

doi:10.1021/acs.jmedchem.9b00271

Cited by 16 publications

(51 citation statements)

References 25 publications

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“…As the initiating protease of the classical pathway, C1r catalyzes the first proteolytic cleavage event and thus represents the most upstream enzymatic target of the pathway. While complement-directed therapeutics continue to be dominated by antibody-based drugs, small-molecules have recently seen two major breakthroughs in the successful development of factor B and factor D-specific inhibitors [ 48 , 49 , 50 ]. In general, small-molecule drugs are afforded greater tissue penetrance relative to antibodies/biologics and can more easily cross the blood–brain barrier [ 51 , 52 ].…”

Section: Discussionmentioning

confidence: 99%

“…However, given their low molecular complexity, it is not necessarily expected that fragment hits themselves will exhibit high selectivity [ 36 ]. Nonetheless, it is encouraging that active-site targeted small-molecule inhibitors of other complement serine proteases, factor B and factor D, have ultimately overcome this same challenge of specificity [ 48 , 49 , 50 ]. Although our C1r-domain mapping and molecular dynamics studies have provided information about CMP-1696, defining the binding mode of each fragment hit identified here—including CMP-1611 using empirical experimental methods, such as x-ray crystallography coupled with rigorous MD simulations—is a key next step being actively pursued in our laboratory.…”

Section: Discussionmentioning

confidence: 99%

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Targeting the Initiator Protease of the Classical Pathway of Complement Using Fragment-Based Drug Discovery

et al. 2020

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The initiating protease of the complement classical pathway, C1r, represents an upstream and pathway-specific intervention point for complement-related autoimmune and inflammatory diseases. Yet, C1r-targeted therapeutic development is currently underrepresented relative to other complement targets. In this study, we developed a fragment-based drug discovery approach using surface plasmon resonance (SPR) and molecular modeling to identify and characterize novel C1r-binding small-molecule fragments. SPR was used to screen a 2000-compound fragment library for binding to human C1r. This led to the identification of 24 compounds that bound C1r with equilibrium dissociation constants ranging between 160–1700 µM. Two fragments, termed CMP-1611 and CMP-1696, directly inhibited classical pathway-specific complement activation in a dose-dependent manner. CMP-1611 was selective for classical pathway inhibition, while CMP-1696 also blocked the lectin pathway but not the alternative pathway. Direct binding experiments mapped the CMP-1696 binding site to the serine protease domain of C1r and molecular docking and molecular dynamics studies, combined with C1r autoactivation assays, suggest that CMP-1696 binds within the C1r active site. The group of structurally distinct fragments identified here, along with the structure–activity relationship profiling of two lead fragments, form the basis for future development of novel high-affinity C1r-binding, classical pathway-specific, small-molecule complement inhibitors.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Targeting the Initiator Protease of the Classical Pathway of Complement Using Fragment-Based Drug Discovery

et al. 2020

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“…Complement dysregulation can occur as a result of genetic mutations or the development of autoantibodies to components of the system, both of which can lead to erroneous activation or insufficient control of pathway signaling ( 4 , 51 ). Therefore, screening for mutations in components of the complement system can be important for diagnosing some complement-driven diseases ( 3 ) and may even help to inform treatment decisions.…”

Section: Dysregulation Of Complement Activation In Autoimmune Diseases Where the Alternative Complement Pathway Plays An Important Rolementioning

confidence: 99%

Complement Factor D as a Strategic Target for Regulating the Alternative Complement Pathway

Barratt

Weitz

2021

Front. Immunol.

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The complement system is central to first-line defense against invading pathogens. However, excessive complement activation and/or the loss of complement regulation contributes to the development of autoimmune diseases, systemic inflammation, and thrombosis. One of the three pathways of the complement system, the alternative complement pathway, plays a vital role in amplifying complement activation and pathway signaling. Complement factor D, a serine protease of this pathway that is required for the formation of C3 convertase, is the rate-limiting enzyme. In this review, we discuss the function of factor D within the alternative pathway and its implication in both healthy physiology and disease. Because the alternative pathway has a role in many diseases that are characterized by excessive or poorly mediated complement activation, this pathway is an enticing target for effective therapeutic intervention. Nonetheless, although the underlying disease mechanisms of many of these complement-driven diseases are quite well understood, some of the diseases have limited treatment options or no approved treatments at all. Therefore, in this review we explore factor D as a strategic target for advancing therapeutic control of pathological complement activation.

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“…Clinical observations support this hypothesis given that Adipsin levels are elevated in post-menopausal women with associated low BMD (67) and circulating levels of Adipsin and associated complement proteins fluctuate in response to food intake changes in patients with anorexia nervosa (68). As a major regulator of the complement system, current pharmacological advancements include the synthesis and preclinical characterization of Adipsin inhibitors targeting the alternative complement pathway (69). For example, an anti-Adipsin antibody has been developed for the purpose of treating geographic atrophy (70).…”

Section: Discussionmentioning

confidence: 91%

Adipsin promotes bone marrow adiposity by priming mesenchymal stem cells

Aaron

Kraakman

et al. 2021

Preprint

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Background: Bone marrow (BM) adipose tissue (BMAT) has been shown to be vital for regulating metabolism and maintaining skeletal homeostasis in the marrow niche. As a reflection of BM remodeling, BMAT is highly responsive to nutrient fluctuations, hormonal changes and metabolic disturbances such as obesity and diabetes mellitus. Expansion of BMAT has also been strongly associated with bone loss in mice and humans. However, the regulation of BM plasticity remains poorly understood, as does the mechanism that links changes in marrow adiposity with bone remodeling. Methods: Using C57BL/6 mice as a model, we employed the bone-protected PPARg constitutive deacetylation (2KR), Adipsin, and its downstream effector, C3, knockout mice. These mice were challenged to thiazolidinedione treatment, calorie restriction, or aging in order to induce bone loss and MAT expansion. Analysis of bone density and marrow adiposity was performed using a μCT scanner and by RNA analysis to assess adipocyte and osteoblast markers. For in vitro studies, primary bone marrow stromal cells (BMSCs) were isolated and subjected to osteoblastogenic or adipogenic differentiation or chemical treatment followed by morphological and molecular analyses. Clinical data was obtained from samples of a previous clinical trial of fasting and high calorie diet in healthy human volunteers. Results: We have shown that Adipsin is the most up-regulated adipokine during BMAT expansion in mice and humans, in a PPARg acetylation-dependent manner. Ablation of Adipsin in mice specifically inhibited BMAT expansion but not peripheral adipose depots, and improved bone mass during calorie restriction, thiazolidinedione treatment, and aging. These effects were mediated through its downstream effector, complement component C3, to prime common progenitor cells toward adipogenesis rather than osteoblastogenesis through inhibiting Wnt/b-catenin signaling. Conclusions: Adipsin promotes new adipocyte formation and affects skeletal remodeling in the BM niche. Our study reveals a novel mechanism whereby the BM sustains its own plasticity through paracrine and endocrine actions of a unique adipokine. Funding: This work was supported by the National Institutes of Health T32DK007328 (NA), F31DK124926 (NA), R01DK121140 (JCL), R01AR068970 (BZ), R01AR071463 (BZ), R01DK112943 (LQ), and P01HL087123 (LQ).

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Design, Synthesis, and Preclinical Characterization of Selective Factor D Inhibitors Targeting the Alternative Complement Pathway

Cited by 16 publications

References 25 publications

Targeting the Initiator Protease of the Classical Pathway of Complement Using Fragment-Based Drug Discovery

Targeting the Initiator Protease of the Classical Pathway of Complement Using Fragment-Based Drug Discovery

Complement Factor D as a Strategic Target for Regulating the Alternative Complement Pathway

Adipsin promotes bone marrow adiposity by priming mesenchymal stem cells

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