A targeted analysis to study synaptic plasticity in cerebellum and hippocampus showed reduced Gabra1 and Gabra5 expression levels in females, whereas Gabra1 expression was increased in males, suggesting an opposite, sex-dependent regulation of the GABA receptor expression already described in humans. In conclusion, the novel Cdkl5E364X mouse model is characterized by robust neurological and neurobehavioral alterations, associated with a molecular profile related to synaptic function indicative of a cerebellar GABAergic hypofunction, pointing to Gabra1 and Gabra5 as novel druggable target candidates for CDD.

EphrinB2 enhanced the transcriptional activity of ISL1 at the VEGFR3 (FLT4) promoter, and VEGFR3 inhibitor MAZ51 significantly diminished the EphrinB2-mediated lymphangiogenesis and deteriorated the ischemic cardiac function. We uncovered a novel mechanism of EphrinB2-driven cardiac lymphangiogenesis in improving myocardial remodeling and function after MI.

Inhibiting PI3K/Akt with LY294002, Capivasertib (AZD5363), or using an inactive Akt mutant significantly increased p35 expression and subsequently enhanced AR stability and activation in PCa cells. Importantly, CDK5 knockdown further reduced PI3K/Akt-inhibition-induced AR and cell viability maintenance, suggesting a compensatory role for CDK5-AR in maintaining cell viability under Akt inhibition. In conclusion, PI3K/Akt inhibition could trigger p35-CDK5-dependent AR activation and cell viability, highlighting p35-CDK5 as a critical link connecting PI3K/Akt inhibition to AR activation and pivotal in PCa cell resistance to PI3K/Akt blockade.

P=N/A, N=8, Recruiting, Xuanwu Hospital, Beijing | Not yet recruiting --> Recruiting | Initiation date: Jun 2024 --> Sep 2024

Silencing Cdk5 or Mcm2 suppressed cell proliferation and colony formation in the 293T cell lines. Therefore, our findings provide a new mouse model of intermediate lobe-originated pituitary adenoma induced by p25/Cdk5 and unveil a previously unappreciated role of Cdk5 and Mcm2 in pituitary adenoma tumorigenesis.

N-acetylcysteine (NAC), roscovitine and Mdivi-1 ameliorated SE-induced PV neuronal degeneration by mitigating CDK5 Y15 hyperphosphorylation, aberrant mitochondrial fragmentation and reduced GPx1-mediated NF-κB inhibition. Furthermore, SN50 (a NF-κB inhibitor) alleviated SE-induced PV neuronal degeneration, independent of dysregulation of mitochondrial fission, CDK5 hyperactivation and GPx1 downregulation. These findings provide an evidence that oxidative stress may activate CDK5-DRP1- and GPx1-NF-κB-mediated signaling pathways, which would be possible therapeutic targets for preservation of PV neurons in various diseases.

Treatment with roscovitine-a clinically applicable Cdk5 inhibitor-alone or combined with immune checkpoint inhibitors, significantly reduces BrM burden and increases tumour-infiltrating functional CD8+ lymphocytes in mice. Thus, astrocyte-induced Cdk5 overexpression endorses BrM immune evasion, whereas therapeutically targeting Cdk5 markedly improves the efficacy of immune checkpoint inhibitors and inhibits BrM growth.

P3, N=20, Not yet recruiting, Marinus Pharmaceuticals | Trial completion date: Dec 2024 --> Mar 2027 | Trial primary completion date: Dec 2024 --> Dec 2026

CDK5RAP3 exhibits a clear regulatory role in vascular regeneration, as downregulating its expression in endothelial cells enhances VEGF synthesis and subsequently improves cell migration and lumen formation capability. This study presents evidence indicating that moderate hypoxia facilitates angiogenesis by inhibiting CDK5RAP3, demonstrating the potential for CKD5RAP3 to be a potent antiangiogenic agent in angiogenesis regulation of cancer, ischemic diseases, and wound healing.

Importantly, high protein levels of MORC2, RBM39 and Slug are strongly associated with metastasis and poor clinical outcomes of colorectal cancer patients. Taken together, our findings uncover a novel mechanism by which MORC2 promotes colorectal cancer metastasis, through RBM39-mediated pre-CDK5RAP2 alternative splicing and highlight the MORC2/RBM39/CDK5RAP2 axis as a potential therapeutic target for colorectal cancer.

Furthermore, Prasugrel was identified as a candidate USP1 inhibitor for targeting the phenotypes of HCC by an extensive computational study combined with experimental validations. Taken together, USP1 induced malignant phenotypes and metabolic reprogramming by modulating mitochondrial dynamics in a CDK5-mediated Drp1 phosphorylation manner, thereby deteriorating HCC progression.

P=N/A, N=8, Not yet recruiting, Xuanwu Hospital, Beijing

P=N/A, N=20, Recruiting, University of Milan

In addition, TSPAN6 overexpression in glioblastoma cells enhanced angiogenesis via regulating TME and STAT3 signaling pathway. Collectively, TSPAN6 has the potential to serve as both a therapeutic target and a prognostic biomarker for the treatment of glioblastoma.

Selectivity profiling against 11 homologous kinases revealed multikinase inhibition (CDK2, CDK5, CDK9, and GSK-3α/β), most potent for GSK-3α in the nanomolar range (IC50s ∼ 0.23-0.98 μM). These compounds may therefore have diverse anticancer mechanisms of action and are of considerable interest for lead optimization.

In summary, our study elucidates that metformin inhibits sympathetic neuronal differentiation in PC12 cells by disrupting TrkA/ERK/EGR1 and p35/CDK5 signaling. This research contributes to uncovering a novel signaling mechanism in drug response during sympathetic neuronal differentiation, enhancing our understanding of the intricate molecular processes governing this critical aspect of neurodevelopment.

Several potent small molecule inhibitors, exemplified by TG02 (4), have progressed to clinical trials...Our focus extends to various types of inhibitors, including pan-inhibitors, selective inhibitors, dual-target inhibitors, degraders, PPI inhibitors, and natural products. The discussion encompasses chemical structures, structure-activity relationships (SARs), biological activities, selectivity, and therapeutic potential, providing detailed insight into the diverse landscape of CDK9 inhibitors.

CDK5 might play important roles in bladder cancer progression and be a potential diagnostic and therapeutic target in the near future.

TG02 exhibits overlapping toxicity with alkylating agents and low single agent clinical activity in recurrent glioblastoma. The role of CDK-9 and its down-stream effectors as prognostic factors and therapeutic targets in glioblastoma warrants further study.

Targeting CDK5 can synergize with PD-1 blockade to suppress HCC growth, which may have clinical benefits. Our study reveals a unique regulation of the degradation of PD-L1 in HCC, and provides an attractive therapeutic target, a potential drug, and a new prognostic marker for the clinical treatment of HCC.

CDK5 thus acts as a molecular rheostat, with different activity levels eliciting distinct functional outcomes. Finally, as CDK5's role is defined by its substrates, targeting them individually or in conjunction with CDK5 should create potentially valuable new clinical opportunities.

Based on data from the Phase 3 study, the efficacy, safety, and drug exposure appear similar between patients administered GNX orally and via g-tube. Olson et al. Pediatr Neurol.

The three most frequent seizure-related ICD-10 diagnoses beyond CDD were “Lennox-Gastaut Syndrome,” followed by “epilepsy, unspecified,” and “other generalized epilepsy and epileptic syndromes.” The most common medications discontinued prior to ganaxolone prescription were levetiracetam, topiramate, phenobarbital, and valproate. The most common concomitant medications were clobazam, levetiracetam, cannabidiol, and valproate... This real-world clinical prescribing data provides valuable insights into the population of CDD patients that healthcare providers are intending for ganaxolone use as the next line of antiseizure therapy. Early prescription data suggests use across the spectrum of seizure burden including many patients with highly refractory epilepsy. These results represent the first step in establishing evidence surrounding the real-world use of ganaxolone to help further inform clinical decision-making for providers treating patients with CDD.

Supported by Marinus Pharmaceuticals

Our findings reveal that CDK5 promotes cell apoptosis by stabilizing DP1 and activating E2F1 signaling, suggesting its potential role in the prognosis and therapeutic decisions for patients with gastric cancer.

Groups A and B explored the maximum tolerated dose (MTD) of TG02 in elderly patients with IDH1R132H-non-mutant newly diagnosed glioblastoma or anaplastic astrocytoma, in combination with hypofractionated radiotherapy alone (group A) or temozolomide alone (group B), based on O6-methylguanine DNA methyltransferase promoter methylation status determined centrally. Larger randomized trials are required to explore activity in combination with RT or TMZ. The role of CDK-9 and its down-stream effectors as prognostic factors and therapeutic targets in glioblastoma warrants further study.

These findings identify the miR152-CDK5R1 signaling axis as a critical mechanism for tumorigenesis that may serve as a new therapeutic target in Ewing's sarcoma. We believe that our results will aid in the development of effective treatment strategies for patients with ES.

The results also showed that milciclib might inhibit the proliferation and migration of KYSE150 and KYSE510 cells by targeting CDKN2A. In conclusion, the abovementioned CUGs and CRGs play a crucial role in tumorigenesis and cancer progression in ESCC, indicating their potential as therapeutic targets.

Our findings highlight the potential of CDKS as a prognostic biomarker and an indicator of immunotherapy response in gastric cancer patients. Moreover, our study suggests that targeting CDK5 could provide a new pathway for exploring immunotherapeutic research.

TP5 alone or in combination with irinotecan increased mitochondrial ROS levels and inhibited tumor growth, prolonging mouse survival in the CRC xenograft animal model. These results suggest that TP5, either alone or in combination with irinotecan, is a promising therapeutic option for colorectal carcinoma.

The disruption of the CDC2/cyclin B1 complex suggested that SFN may have antitumor effects on established breast adenocarcinoma cells. Our findings suggest that, in addition to its chemopreventive properties, SFN could be used as an anticancer agent for breast cancer, as it was found to inhibit growth and induce apoptosis of cancer cells.

Tamoxifen, the gold standard drug for endocrine therapy for breast cancer, modulates the phosphorylation status of the TAU protein in Alzheimer's disease by inhibiting CDK5 kinase activity...This encouraging alternative opens the way to the ensuing chemical optimization of this scaffold. It also promises a more specific therapeutic approach that may both tackle the pathological signaling in breast cancer and provide a potential new drug for Alzheimer's disease.

Molecular docking analysis and surface plasmon resonance assay suggested that dendrobine directly bound to CDK5 protein with a KD value of 2.05 × 10  M. In summary, alkaloids are the neuroprotective constituents of D. nobile Lindl., and dendrobine protected PC12 cells against Aβ -induced apoptosis by inhibiting CDK5 activation.

High-CDK5 expression was associated with immunosuppression and IO+TKI resistance. RFscore based on CDK5 may be utilized as a biomarker to determine the optimal treatment strategy.

P1/2; Not yet recruiting --> Recruiting | Trial completion date: Aug 2027 --> Aug 2029 | Trial primary completion date: Aug 2023 --> Aug 2025

High PRMT1 protein expression is associated with elevated mTORC1 signaling in patients with HCC. Thus, our study dissects a phosphorylation- and arginine methylation-dependent regulatory mechanism of mTORC1 activation and tumor growth and provides a molecular basis to target this pathway for cancer therapy.

Mechanistically, YTHDF1 promotes the expression of multiple oncogenes by binding to their mRNAs and enhancing mRNA stability and translation in retinoblastoma cells. Taken together, our findings reveal a novel MYCN-YTHDF1 regulatory cascade in controlling retinoblastoma cell proliferation and tumor growth, pinpointing an unprecedented mechanism for MYCN amplification and/or activation to promote retinoblastoma progression.

We found that less-selective CDKIs, including flavopiridol, roscovitine, dinaciclib, and SNS-032, induced DR5 via p73-mediated transcriptional activation...CDKIs strongly synergized with 5-fluorouracil (5-FU), the most commonly used CRC chemotherapy agent, in vitro and in vivo to promote growth suppression and apoptosis, which required DR5 and p73. Together, these findings indicate p73-mediated DR5 induction as a potential tumor suppressive mechanism and a critical target engaged by different CDKIs in potentiating therapy-induced apoptosis in CRC cells. These findings help better understand the anticancer mechanisms of CDKIs and may help facilitate their clinical development and applications in CRC.

The potential enantioselectivity of MDPV in cytotoxicity and in the expression of neuroplasticity-involved proteins-brain-derived neurotrophic factor (BDNF) and cyclin-dependent kinase 5 (Cdk5)-was also evaluated using SH-SY5Y neuroblastoma cells. No enantioselectivity was observed.

Pharmacologically targeting the CDK5 or ACSS2 with respective small molecule inhibitors reduces tumor growth in orthotopic ex vivo brain slice model. These results suggest a crucial role for OGT/CDK5/ACSS2 signaling axis to regulate lipid metabolism in BCBM cells and identify CDK5 and ACSS2 as novel therapeutic targets for treatment of breast cancer brain metastatic growth.

We validated HiBiT tagging of P3F and not the wild-type FOXO1 by Western analysis. We showed that the HiBiT tag did not change the function of P3F by transducing human fibroblasts with P3F-HiBiT versus unmodified P3F. Gene Set Enrichment Analysis (GSEA) of RNA-seq showed that P3F-HiBiT activated the same downstream target genes as unmodified P3F.