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.

Cross-referencing previous research, we tried to map these molecular components onto potential pathways, and we may provide important new information on molecular mechanisms of neuronal differentiation induced by PACAP. Gene and protein expression data are publicly available at NCBI GSE223333 and ProteomeXchange, identifier PXD039992.

The chromone alkaloids, majorly rohitukine and its analogues were closely clustered with flavopiridol, P-276-00 and IIIM-290 along with other chrotacumines in the chemical phylogeny. In conclusion, D. binectariferum is a rich source of chromone alkaloids, which could lead to the discovery of more potential scaffolding for CDK inhibitors as anticancer drugs.

Some other ERK target proteins, such as pyruvate kinase M2 and hypoxia-inducible transcription factor-1, are also transported to the nucleus via the Pin1-Hsp90α system to modulate gene expression and energy metabolism. Notably, as malignant tumors often express enhanced Pin1-Hsp90α signaling pathways, this provides a potential therapeutic target for tumors.

BRD4-targeted drug PFI-1 and (BRD2, BRD3, and BRD4)-targeted drug I-BET-151 may have good inhibitory effects on the SW13 cell line. The findings of this study provide a partial basis for the role of BRD2, BRD3, and BRD4 in the occurrence and development of ACC. In addition, this study also provides new potential therapeutic targets for ACC, which can serve as a reference for future basic and clinical research.

According to the L1000CDS2 database, potential targeting drugs were found to reverse the expressions of DEGs, with panobinostat (S1030) validated effective for tumor repression in MTC by in vitro experiments...Additionally, a high hub-gene score or a low miRNA score indicated good prognoses of neuroendocrine tumors. The present study uncovers underlying molecular mechanisms and potential immunotherapy-related targets for the pathogenesis and drug discovery of MTC.

This combination eradicated leukemic blasts within hypodiploid ALL PDX mice with low off-target toxicity. Our findings suggest that dual inhibition of BCL-2 (venetoclax) and CDK9/MCL-1 (dinaciclib) is a promising therapeutic approach in hypodiploid ALL, warranting further investigation to inform clinical trials in this high-risk patient population.

To address the need for improved Pol I inhibitors with minimal off-target effects we collaborated with Pimera Inc to develop a selective 2nd-generation Pol I inhibitor, PMR-116. We show that combinatorial therapy with CX-5461 and both Flavopiridol and Dinaciclib have a synergistic effect in vitro and significantly increase the survival of acute myeloid leukaemia (AML) models in vivo. Our data indicates that inhibition of both Pol I (by CX-5461) and Pol II (by CDK9 inhibitors) can be used in as a therapy to extend survival and reduce acquired resistance.

In addition, CDK1, CDC20, CCNA2, CCNB1 and CCNB2 expressions may be involved in the regulation of monocytes and tumor-associated macrophages (TAMs) in HCC, respectively. These findings strongly suggested that cell cycle-related genes could be used as novel biomarkers for exploring the prognosis and immune cells infiltration of HCC.

As proof of concept for this strategy, we identified docetaxel, biscurcumin, primaquine, and doxorubicin as potential exosome release inhibitors in the Her-2 positive MDA-MB-453 and luminal A MCF7 cell lines. Dinaciclib also functioned as an exosome release inhibitor in MCF7 cells. Further, we explored the expression of proteins involved in exosome biogenesis (TSG101, CD9 tetraspanin, Alix, SMase2) and release (Rab11, Rab27) to decipher and validate the possible molecular mechanisms of action of the identified exosome inhibitors. We anticipate that our approach could help to create robust high-throughput screening methodologies to accelerate drug repurposing when using FDA-approved compound libraries and to develop rationally-designed single/combination therapies (including nanomedicines) that can target metastasis progression by modulating exosome biogenesis or release in various tumor types.

Dinaciclib improves the sensitivity of cervical cancer cells to IR by inducing cell cycle arrest, delaying DNA repair, and increasing apoptosis. However, further research is needed to unravel the complexity of DNA repair pathways.

P2, N=28, Not yet recruiting, Tiziana Life Sciences LTD

Antiproliferative activity of 5 in 3D multicellular tumor spheroid model of cancer cells (HCT116, LS-174) superior to that of cisplatin was found. Moreover, HL and 5 showed notable inhibition potency against glycogen synthase kinases (GSK-3α and GSK-3β), tyrosine-protein kinase (Src), lymphocyte-specific protein-tyrosine kinase (Lck), and cyclin-dependent kinases (Cdk2 and Cdk5) (IC = 1.4-6.1 μM), suggesting their multitargeted mode of action as potential anticancer drugs.

- Etiology of genetic WS is diverse. Down syndrome, CDKL5, ALDH7A1, SCN1A and KCNQ2 are common causes of genetic WS. - Fragile X syndrome and Mitochondrial inherited disorder can cause WS.