Delving into the Latest Updates on KN-93 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

KN-93

Target

CaMKII

Action

inhibitors

Mechanism

CaMKII inhibitors(Calcium/Calmodulin dependent protein kinase II inhibitors)

Therapeutic Areas

Nervous System DiseasesCongenital DisordersOther Diseases

Active Indication-

Inactive Indication

Charcot-Marie-Tooth Disease

Originator Organization

Repositioning Investments Ltd.

Active Organization-

Inactive Organization

Repositioning Investments Ltd.

License Organization-

Drug Highest PhasePendingDiscovery

First Approval Date-

Regulation-

Structure/Sequence

Molecular FormulaC26H29ClN2O4S

InChIKeyLLLQTDSSHZREGW-UHFFFAOYSA-N

CAS Registry139298-40-1

Oxa-resistant HCT116 and HT29 sublines (HCT116-Oxa and HT29-Oxa) were established through gradual dose escalation. The activation status of the Ca²⁺/CaM/CaMKII pathway was assessed by measuring intracellular Ca²⁺ levels and phosphorylation of CaMKII. Functional studies such as CCK-8, clonogenic assays, and flow cytometry-based apoptosis analysis were conducted to assess the impact of CaMKII inhibition by KN-93 on chemosensitivity. Gain-of-function experiments were conducted using CaMKII-overexpressing HT29 cells. The in vivo antitumor efficacy was evaluated using an HCT116-Oxa xenograft model in BALB/c nude mice treated with Oxa, KN-93, or a combination of both.

RESULTS:

Oxa-resistant cells exhibited significantly elevated IC₅₀ values, increased basal intracellular Ca²⁺ levels, and hyperphosphorylation of CaMKII. Pharmacological inhibition of CaMKII with KN-93 enhanced Oxa-induced cytotoxicity, suppressed clonogenic survival, and promoted apoptosis in resistant cells, accompanied by downregulation of p-RAF and p-ERK. Overexpression of CaMKII in parental HT29 cells conferred resistance to Oxa and attenuated drug-induced apoptosis. In vivo, combination therapy with Oxa and KN-93 significantly inhibited tumor growth compared to monotherapy, without increasing systemic toxicity. Western blot analysis confirmed reduced phosphorylation of CaMKII and ERK in tumor tissues from the combination group.

CONCLUSION:

Hyperactivation of the Ca²⁺/CaM/CaMKII pathway contributes to Oxa resistance in CRC, at least in part via RAF-ERK signaling. Targeting CaMKII may be a viable strategy to overcome resistance.

01 Jul 2026·OSTEOARTHRITIS AND CARTILAGE

microRNA-544a-3p as a new modulator of the Wnt-signalling network in the articular cartilage and osteoarthritis

Article

Author: Hueniken, Katrina ; Santos, Keemo Delos ; Kapoor, Mohit ; Swingler, Tracey ; Heluany, Cintia Scucuglia ; Clark, Ian ; Day, Nicholas James ; De Palma, Anna ; Sochart, David ; Nalesso, Giovanna

OBJECTIVE:

Determining the effect of microRNA-544a-3p (miR-544a-3p) in articular chondrocytes isolated from patients affected by osteoarthritis (OA) and its role in the modulation of the Wnt signalling.

METHOD:

Articular chondrocytes were isolated from patients undergoing joint replacement because of OA. Expression levels of miR-544a-3p were measured by PCR and in situ hybridization. Putative targets of miR-544a-3p were confirmed by reporter assay and qPCR in cells stimulated with a miR-544a-3p mimic. The effect of miR-544a-3p on chondrocyte metabolism was monitored by qPCR for phenotypic markers, protein expression levels of aggrecan neoepitopes/MMP-13 and modulation of proteoglycan content in micromass cultures, upon stimulation with a miR-544a-3p mimic. The expression levels of MMP-13 and Aggrecan neoepitopes in response to miR-544a-3p stimulation was also measured in co-stimulation with XAV-939 and KN93, respectively β-catenin and CaMKII inhibitors.

RESULTS:

Our results suggest that miR-544a-3p enhances the activation of the Wnt-signalling in articular chondrocytes. The expression of miR-544a-3p is higher in chondrocytes isolated from damaged (median difference Hodges-Lehman, damaged vs preserved, 1.480, 95%CI, 0.1794-2.784, p=0.0097) areas of the articular cartilage removed from OA patients, and can be upregulated by pro-inflammatory cytokines. miR-544a-3p exerts a pro-catabolic effect on articular chondrocytes, which is rescued both by the inhibition of the Wnt/β-catenin and Wnt/CaMKII signalling pathways.

CONCLUSION:

Our results point to miR-544a-3p as a new, important modulator of the Wnt signalling network within the articular cartilage suggesting a key role for microRNAs in regulating how the multiple branches of the network and their interaction modulate cartilage homeostasis.

03 Jun 2026·NEUROLOGICAL RESEARCH

Electroacupuncture activation of the CaMKII/CREB pathway improves dLGN synaptic plasticity in monocular deprivation amblyopic rats

Article

Author: Li, Qinghong ; Hu, Chenying ; Ding, Jian ; Ji, Yangbin ; Wang, Lin ; Yang, Xuefei

OBJECTIVE:

This study aimed to investigate the therapeutic potential of electroacupuncture(EA) for amblyopia, a common childhood visual disorder caused by early abnormalities such as monocular deprivation(MD). We examined the role of the calcium/calmodulin-dependent protein kinase II/cAMP response element-binding protein(CaMKII/CREB) pathway and enhanced synaptic plasticity in visual function improvement following EA.

METHODS:

An amblyopia model was established using 14-day-old rats by inducing MD during a critical developmental period. MD rats received EA stimulation at the Cuanzhu(BL2) and Fengchi(GB20) acupoints for 14 consecutive days. Visual function was assessed. Structural damage to the retina and dorsal lateral geniculate nucleus(dLGN) was analyzed. CaMKII/CREB pathway and synaptic plasticity proteins(SYN1 and PSD95) activity levels were measured. To confirm CaMKII involvement, the inhibitor KN93 was administered.

RESULTS:

EA was associated with significant visual function improvement in rats MD with and reduced structural damage to retinal and dLGN cells. EA activated the CaMKII/CREB signaling pathway and upregulated synaptic plasticity protein(SYN1 and PSD95) expression. The therapeutic effects of EA were markedly attenuated when the CaMKII inhibitor KN93 was co-administered, demonstrating that CaMKII signaling is essential for mediating the benefits of EA.

CONCLUSION:

EA effectively treated amblyopia in this model by restoring visual function and protecting neural structures by activating the CaMKII/CREB signaling pathway, subsequently enhancing synaptic plasticity. These findings provide a strong theoretical foundation for the clinical application of EA in the treatment of amblyopia.

100 Deals associated with KN-93

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