SM04755, a small‐molecule inhibitor of the Wnt pathway, as a potential topical treatment for tendinopathy

Abstract

The Wnt pathway is upregulated in tendinopathy, affecting inflammation and tenocyte differentiation. Given its potential role in tendinopathy, this signaling pathway may be a relevant target for treatment. The current study examined the therapeutic potential of SM04755, a topical, small-molecule Wnt pathway inhibitor, for the treatment of tendinopathy using in vitro assays and animal models. In vitro, SM04755 decreased Wnt pathway activity, induced tenocyte differentiation, and inhibited catabolic enzymes and pro-inflammatory cytokines in human mesenchymal stem cells, rat tendon-derived stem cells, and human peripheral blood mononuclear cells. Evaluation of the mechanism of action of SM04755 by biochemical profiling and computational modeling identified CDC-like kinase 2 (CLK2) and dualspecificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) as molecular targets. CLK and DYRK1A inhibition by siRNA knockdown or pharmacological inhibition induced tenocyte differentiation and reduced tenocyte catabolism. In vivo, topically applied SM04755 showed therapeutically relevant exposure in tendons with low systemic exposure and no detectable toxicity in rats. Moreover, SM04755 showed reduced tendon inflammation and evidence of tendon regeneration, decreased pain, and improved weight-bearing function in rat collagenase-induced tendinopathy models compared with vehicle control. Together, these data demonstrate that CLK2 and DYRK1A inhibition by SM04755 resulted in Wnt pathway inhibition, enhanced tenocyte differentiation and protection, and reduced inflammation. SM04755 has the potential to benefit symptoms and modify disease processes in tendinopathy.

Dual-Specificity, Tyrosine Phosphorylation-Regulated Kinases (DYRKs) and cdc2-Like Kinases (CLKs) in Human Disease, an Overview

“…Alternative splicing of Tau exon 10 is regulated by CLK2 and other CLKs, leading to changes in the 3R/4R isoform ratio and neurodegeneration in sporadic AD [ 224 , 225 ]. Dual inhibitions of CLK2 and DYRK1A by Lorecivivint (SM04690) and by its analogue SM04755 are potential disease-modifying approaches for knee osteoarthritis [ 193 , 194 ] and for tendinopathy, respectively [ 195 ]. CLK2 inhibition compromises MYC-driven breast tumors, triple-negative breast cancer, and glioblastoma.…”

“…Tendinopathy [195] DYRK1A Human immunodeficiency virus type 1 (HIV-1) [196][197][198] DYRK1A DYRK1B Human cytomegalovirus (HCMV) [199] DYRK1B…”

Development of Cdc2-like Kinase 2 Inhibitors: Achievements and Future Directions

“…It has entered phase 1 trials as an oral pan-CLK inhibitor (CLK2 IC 50 = 2 nM) for the treatment of advanced solid tumors. , Notably, CLK3 (IC 50 = 22 nM) was also inhibited by compound 4 . Recently, Biosplice reported that indazole-3-carboxamide derivative 5 (SM04755, Table , Figure A) guided by a structure–activity relationship (SAR) exhibited picomolar activity in enzymatic assays (CLK2 IC 50 = 0.822 nM) and lower nanomolar activity in cellular assays (cell CLK2 EC 50 = 268.1 nM). − Docking studies suggested that 5 formed hydrogen bonds with Glu244, Leu246, and Lys193 in the ATP-binding site of CLK2 . However, the phase 1 trial for the treatment of plaque psoriasis was terminated based on various commercial factors…”

“…Conversely, dysregulated alternative splicing can be a root cause of developmental disorders, tissue degeneration, and cancer . Owing to their pivotal role, pharmacological inhibitors of CLK2 have been regarded as potential drugs for various diseases including inflammation (e.g., osteoarthritis, tendinopathy), cancers (e.g., triple-negative breast cancer), neurodegenerative diseases (e.g., Alzheimer’s disease), and metabolic diseases (e.g., diabetes). ,,, …”

Discovery of 1-Benzoyl 4-Phenoxypiperidines as Small-Molecule Inhibitors of the β-Catenin/B-Cell Lymphoma 9 Protein–Protein Interaction

“…Much effort has been devoted to discovering inhibitors of the Wnt/β-catenin signaling pathway . Among them, porcupine inhibitors (LGK-974, RXC004, CGX1321, and ETC-159), Fzd receptor-related monoclonal antibodies (OMP-18R5 and OMP-54F28), CREB-binding protein (CBP)/β-catenin inhibitors (PRI-724 and CWP232291), and CLK2 and DYRK1A inhibitors (SM04690, , SM04755, and SM08502) have been tested in the clinic. Most of these reported inhibitors, also including tankyrase inhibitors (XAV939), target the upstream effectors of Wnt/β-catenin signaling, − whereas these agents are forecasted to be ineffective toward the diseases related with more downstream APC and Axin inactivation mutations or β-catenin activation mutations.…”