A small-molecule inhibitor of the Wnt pathway (SM04690) as a potential disease modifying agent for the treatment of osteoarthritis of the knee

Deshmukh, V.; Hu, H.; Barroga, Charlene F.; Bossard, Carine; Kc, Sunil; Dellamary, Luis; Stewart, Joshua; Chiu, Kevin; Ibanez, Maureen; Pedraza, M.; Seo, T.; Do, Long; Cho, S.; Cahiwat, Joseph; Tam, Betty; Tambiah, J.; Hood, John; Lane, Nancy E.; Yazıcı, Yusuf

doi:10.1016/j.joca.2017.08.015

Cited by 180 publications

(164 citation statements)

References 47 publications

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“…Systemic levels of the drug were extremely low. Intra-articular injection also provided clear protection against osteoarthritis development in rats both in a surgical instability model [42] and in model characterized by inflammation and pain [43], thus paving the way for human trials.…”

Section: Lorecivivint Is a Small Molecule Wnt Pathway Inhibitormentioning

confidence: 97%

“…The important role of Wnt signaling in a number of diseases, including osteoarthritis and osteoporosis, has sparked interest from pharmaceutical and biotechnology companies to target the pathway for the treatment of these disorders. In a drug library screening, different Wnt modulators were identified of which lorecivivint (SM04690) was selected for studies on osteoarthritis [42]. Of note, the -vivint suffix definition has been attributed to the novel class of Wnt pathway inhibitors.…”

Section: Lorecivivint Is a Small Molecule Wnt Pathway Inhibitormentioning

confidence: 99%

“…Preclinical development highlighted the potential of lorecivivint to be used in osteoarthritis. In vitro experiments demonstrated that the addition of lorecivivint to differentiation cultures of human mesenchymal progenitor cells towards cartilage increased chondrogenesis, as demonstrated by increased extracellular matrix accumulation, including proteoglycans and collagens [42]. Further cartilage protection could be conferred by the inhibitory effects of lorecivivint on the expression of tissue destructive enzymes from the matrix metalloproteinase family [42].…”

Section: Lorecivivint Is a Small Molecule Wnt Pathway Inhibitormentioning

confidence: 99%

“…In vitro experiments demonstrated that the addition of lorecivivint to differentiation cultures of human mesenchymal progenitor cells towards cartilage increased chondrogenesis, as demonstrated by increased extracellular matrix accumulation, including proteoglycans and collagens [42]. Further cartilage protection could be conferred by the inhibitory effects of lorecivivint on the expression of tissue destructive enzymes from the matrix metalloproteinase family [42]. Of note, the compound also demonstrated antiinflammatory effects by reducing the expression of cytokines such as interleukin-1b, tumor necrosis factor and interleukin-6 in synovial fibroblasts and in peripheral blood mononuclear cells [43], two groups of cells that can play a role in the inflammatory reaction that is often seen in patients with osteoarthritis.…”

Section: Lorecivivint Is a Small Molecule Wnt Pathway Inhibitormentioning

confidence: 99%

“…Of note, the compound also demonstrated antiinflammatory effects by reducing the expression of cytokines such as interleukin-1b, tumor necrosis factor and interleukin-6 in synovial fibroblasts and in peripheral blood mononuclear cells [43], two groups of cells that can play a role in the inflammatory reaction that is often seen in patients with osteoarthritis. These promising results prompted the use of lorecivivint in in vivo models of osteoarthritis [42]. Remarkable, intra-articular injection resulted in sustained high levels of the molecule over several months, mostly in cartilage and to a far lesser extent in bone.…”

Section: Lorecivivint Is a Small Molecule Wnt Pathway Inhibitormentioning

confidence: 99%

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Review Article: Is Wnt Signaling an Attractive Target for the Treatment of Osteoarthritis?

Lories

Monteagudo

2020

Rheumatol Ther

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Osteoarthritis is the most common chronic joint disease affecting millions of people worldwide and a leading cause of pain and disability. Increasing incidence of obesity and aging of the population are two factors that suggest that the impact of osteoarthritis will further increase at the society level. Currently, there are no drugs available that can manage both structural damage to the joint or the associated pain. Increasing evidence supports the view that the Wnt signaling pathway plays an important role in this disease. The current concept, based on genetic and functional studies, indicates that tight regulation of Wnt signaling in cartilage is essential to keep the joint healthy. In this review, we discuss how this concept has evolved, provide insights into the regulation of Wnt signaling, in particular by Wnt modulators such as frizzled-related protein and DOT1-like histone lysine methyltransferase, and summarize preclinical evidence and molecular mechanisms of lorecivivint, the first Wnt antagonist in clinical development for osteoarthritis.

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Section: Lorecivivint Is a Small Molecule Wnt Pathway Inhibitormentioning

confidence: 97%

Section: Lorecivivint Is a Small Molecule Wnt Pathway Inhibitormentioning

confidence: 99%

Section: Lorecivivint Is a Small Molecule Wnt Pathway Inhibitormentioning

confidence: 99%

Section: Lorecivivint Is a Small Molecule Wnt Pathway Inhibitormentioning

confidence: 99%

Section: Lorecivivint Is a Small Molecule Wnt Pathway Inhibitormentioning

confidence: 99%

See 3 more Smart Citations

Review Article: Is Wnt Signaling an Attractive Target for the Treatment of Osteoarthritis?

Lories

Monteagudo

2020

Rheumatol Ther

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Targeting the CLK2/SRSF9 splicing axis in prostate cancer leads to decreased ARV7 expression

Van Goubergen,

Peřina,

Handle

et al. 2024

Molecular Oncology

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In advanced prostate cancer (PC), in particular after acquisition of resistance to androgen receptor (AR) signaling inhibitors (ARSI), upregulation of AR splice variants compromises endocrine therapy efficiency. Androgen receptor splice variant‐7 (ARV7) is clinically the most relevant and has a distinct 3′ untranslated region (3′UTR) compared to the AR full‐length variant, suggesting a unique post‐transcriptional regulation. Here, we set out to evaluate the applicability of the ARV7 3′UTR as a therapy target. A common single nucleotide polymorphism, rs5918762, was found to affect the splicing rate and thus the expression of ARV7 in cellular models and patient specimens. Serine/arginine‐rich splicing factor 9 (SRSF9) was found to bind to and increase the inclusion of the cryptic exon 3 of ARV7 during the splicing process in the alternative C allele of rs5918762. The dual specificity protein kinase CLK2 interferes with the activity of SRSF9 by regulating its expression. Inhibition of the Cdc2‐like kinase (CLK) family by the small molecules cirtuvivint or lorecivivint results in the decreased expression of ARV7. Both inhibitors show potent anti‐proliferative effects in enzalutamide‐treated or ‐naive PC models. Thus, targeting aberrant alternative splicing at the 3′UTR of ARV7 by disturbing the CLK2/SRSF9 axis might be a valuable therapeutic approach in late stage, ARSI‐resistant PC.

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Unfolding the Mystery Behind the Onset of Chondrocyte Hypertrophy during Chondrogenesis: Toward Designing Advanced Permanent Cartilage‐mimetic Biomaterials

Majumder

Ghosh

2023

Adv Funct Materials

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Successful recapitulation of the anatomical microarchitecture and biomechanics of the native articular cartilage under in vitro culture conditions is still an elusive topic of research. The major roadblock lies in maintaining the stable chondrogenic phenotype in vivo or under long‐term in vitro conditions. Tissue engineers worldwide has coined this aberrant loss of permanent cartilage characteristics to transient cartilage form as “chondrocyte hypertrophy”. Although the following has been validated through the expression of a few known markers but very little is understood regarding the molecular mechanism that dwells underneath. This review summarizes the precise aetiology behind the development and progression of the hypertrophic phenotype in chondrocytes under in vitro chondrogenic conditions. Based on the current literature survey, it is deciphered that the type of cell utilized (chondrocytes or stem cells), the chondrogenic culture conditions (growth factors/biochemical mediators) and the culture microenvironment (oxygen tension, mechanical loading) during chondrogenesis have a direct correlation with the dysregulated activity of the chondrogenic signaling pathways corroborating the onset of hypertrophic maturation of chondrocytes. Furthermore, it is critically analyzed whether to completely inhibit these hypertrophy‐inducing signaling pathways or apply a brake in terms of time‐dependent dose due to their functional duality role in chondrogenesis.

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A small-molecule inhibitor of the Wnt pathway (SM04690) as a potential disease modifying agent for the treatment of osteoarthritis of the knee

Abstract: SM04690 induced chondrogenesis and appeared to inhibit joint destruction in a rat OA model, and is a candidate for a potential disease modifying therapy for OA.

Cited by 180 publications

References 47 publications

Review Article: Is Wnt Signaling an Attractive Target for the Treatment of Osteoarthritis?

Review Article: Is Wnt Signaling an Attractive Target for the Treatment of Osteoarthritis?

Targeting the CLK2/SRSF9 splicing axis in prostate cancer leads to decreased ARV7 expression

Unfolding the Mystery Behind the Onset of Chondrocyte Hypertrophy during Chondrogenesis: Toward Designing Advanced Permanent Cartilage‐mimetic Biomaterials

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