CCT128930 / Otsuka - LARVOL DELTA

Structural basis of selective TRPM7 inhibition by the anticancer agent CCT128930. (PubMed, Cell Rep) - "Moreover, we demonstrate the principal role of several residues in the VL site enabling CCT to inhibit TRPM7 without impacting the homologous TRPM6 channel. Hence, our results uncover the central role of the VL site for the selective interaction of TRPM7 with small molecules that can be explored in future drug design."

Journal • Oncology • TRPM7

PM2.5 induces cardiac malformations via PI3K/akt2/mTORC1 signaling pathway in zebrafish larvae. (PubMed, Environ Pollut) - "Using genetic knockdown and a specific akt2 pharmacological inhibitor, CCT128930, we demonstrated that akt2 activation is essential to EOM-induced heart malformations...Moreover, EOM-induced akt2 activation is mediated via aryl hydrocarbon receptor (AHR)/ROS-induced PTEN inhibition. In conclusion, our results indicate that PM2.5 activates PI3K/akt2/mTORC1 signaling via AHR/ROS-induced PTEN suppression, which leads to mitochondrial-mediated intrinsic apoptosis and Wnt signaling suppression, resulting in cardiac defects in zebrafish larvae."

Journal • Cardiovascular • Heart Failure • AKT2

Targeting Akt/PKB in Pediatric Tumors: A Review From Preclinical to Clinical Trials. (PubMed, Pharmacol Res) - "This review summarizes recent available evidence of Akt inhibitors in pediatric cancers, from both preclinical and clinical studies. In short, we demonstrate the impact that Akt inhibition provides in tumorigenesis, and we suggest targeting the PI3K/Akt/mTOR signaling pathway, alone or in combination with other inhibitors, is a feasible tool to achieve better outcomes in pediatric tumors."

Journal • Preclinical • Review • Oncology • Pediatrics

CDH6 as a prognostic indicator and marker for chemotherapy in gliomas. (PubMed, Front Genet) - "Potential drugs associated with high CDH6 expression were also predicted, including AMG-22, rutin, CCT128930, deforolimus, bis(maltolato)oxovanadium, anagrelide, vemurafenib, CHIR-98014, and AZD5582. Thus, this study showed that CDH6 correlates with glioma immune infiltration, it is expressed mainly in AC-like malignant cells, and it may act as a new target for glioma therapy."

Biomarker • Journal • Brain Cancer • CNS Tumor • Glioma • Infectious Disease • Oncology • Solid Tumor • CD8

Modular photocatalytic synthesis of α-trialkyl-α-tertiary amines (ACS-Fall 2022) - "α-Trialkyl-α-tertiary amines (α-trialkyl-ATAs) – amines with an α-carbon bearing three C–C bonds to aliphatic substituents – represent a subclass of amine that remains particularly challenging to synthesise, despite having proven application in a therapeutic context; examples of α-trialkyl-ATA-containing therapeutic agents include fingolimod (multiple sclerosis), Elayta (Alzheimer’s disease), CCT128930 (AKT inhibitor), and virantmycin (antiviral). Using this methodology it was possible to prepare over 50 new α-trialkyl-ATAs, with excellent functional group tolerance across all three components. These included heterocycles such as tetrahydronaphthyridines, which are valuable but underexplored motifs in medicinal chemistry, as well as a single-step synthesis of Novartis’ multibillion dollar multiple sclerosis drug fingolimod from commercially available starting materials."

Alzheimer's Disease • CNS Disorders • Multiple Sclerosis

CCT128930 is a novel and potent antagonist of TRPM7 channel. (PubMed, Biochem Biophys Res Commun) - "At last, multiple residues in the superficial part of the TRPM7 selectivity filter were identified to be critical for the inhibitory activity of CCT128930 which are different from the determinants of Mg and reported TRPM7 antagonists. Our results indicated that CCT128930 is a novel and potent TRPM7 channel antagonist."

Journal • Neuroblastoma • Oncology • Solid Tumor • TRPM7

CCT128930 induces G1-phase arrest and apoptosis and synergistically enhances the anticancer efficiency of VS5584 in human osteosarcoma cells. (PubMed, Biomed Pharmacother) - "Moreover, CCT128930 treatment obviously enhanced VS5584-induced growth inhibition and apoptosis in human osteosarcoma cells, followed by enhanced PARP cleavage and caspase-3 activation. Taken together, CCT128930 alone or combined treatment with CCT128930 and VS5584 both effectively inhibited human osteosarcoma cells growth by induction of G1-phase arrest and apoptosis through regulating PI3K/mTOR and MAPKs pathways."

Journal • Oncology • Osteosarcoma • Sarcoma • Solid Tumor • CASP3 • CCNB1 • CCND1 • CDK1

Inhibitors of AKT kinase increase LDL receptor mRNA expression by two different mechanisms. (PubMed, PLoS One) - "We have recently shown that MK-2206 and triciribine, two highly selective AKT inhibitors increase the level of low density lipoprotein receptor (LDLR) mRNA which leads to increased amount of cell-surface LDLRs...Here we show that in cultured HepG2 cells, AKT inhibitors ARQ-092, AKT inhibitor VIII, perifosine, AT7867 and CCT128930 increase LDLR mRNA levels by inducing the activity of LDLR promoter...Whereas knockdown of either AKT1 or AKT2 led to upregulation of LDLR promoter activity, only knockdown of AKT2 had a stabilizing effect on LDLR mRNA. Taken together, these results provide strong evidence for involvement of AKT in regulation of LDLR mRNA expression, and point towards the AKT isoform specificity for upregulation of LDLR mRNA expression."

Journal

Dual-Targeting AKT2 and ERK in cancer stem-like cells in neuroblastoma. (PubMed, Oncotarget) - "Blocking these two pathways with specific inhibitors, CCT128930 (AKT2 inhibitor) and PD98059 (MEK inhibitor) decreased cell proliferation, angiogenesis, and cell migration in these resistant cells. Taken together, our findings suggest that CDDP- and radiation-resistant cancer stem-like neuroblastoma cells might serve as a useful tool to improve the understanding of molecular mechanisms of therapeutic resistance. This may aid in the development of more effective novel treatment strategies and better clinical outcomes in patients with neuroblastoma."

Journal

Pivotal Role of AKT2 during Dynamic Phenotypic Change of Breast Cancer Stem Cells. (PubMed, Cancers (Basel)) - "...To confirm the central role of AKT2, we silenced AKT2 expression via small interfering RNA and using a chemical inhibitor (CCT128930), in both CSC and non-CSC from different cancer cell lines...Interestingly, in orthotopic tumor mouse models, high expression levels of AKT2 were detected in circulating tumor cells (CTC). These findings suggest AKT2 as a promising target for future anti-cancer therapies at three important levels: (i) Epithelial-to-mesenchymal transition (EMT) reversion and maintenance of CSC subpopulation in primary tumors, (ii) reduction of CTC and the likelihood of metastatic spread, and (iii) prevention of tumor recurrence through inhibition of CSC tumorigenic and metastatic potential."

Cancer stem cells • Journal

High-concentration hydrogen protects mouse heart against ischemia/reperfusion injury through activation of thePI3K/Akt1 pathway. (PubMed, Sci Rep) - "...C57BL/6 mice were randomly divided into the following groups: sham, I/R, I/R + HCH, I/R + HCH + LY294002 (PI3K inhibitor), I/R + HCH + wortmannin (PI3K inhibitor), I/R + LY294002, and I/R + wortmannin...To investigate the role of Akt1 in the protective effects of HCH, mice were divided into the following groups: I/R + A-674563 (Akt1 selective inhibitor), I/R + HCH + A-674563, I/R + CCT128930 (Akt2 selective inhibitor), and I/R + HCH + CCT128930...HCH resulted in the phosphorylation of Akt1 but not Akt2, and Akt1 inhibition markedly abolished HCH-induced cardioprotection. Our findings reveal that HCH may exert cardioprotective effects through a PI3K-Akt1-dependent mechanism."

Journal • Preclinical

Targeting AKT2 and ERK decline the drug/radiation resistance in neuroblastoma (AACR 2019) - "Blocking these two pathways with chemical inhibitors, CCT128930, AKT2 selective inhibitor and PD98059, MEK inhibitor decreased cell proliferation, angiogenesis, cell migration and soft agar conoly growth in these resistant cells. Our results suggest that selected CDDP-resistant and radiation-resistant neuroblastoma cells might serve as an useful tool to improve understanding of the molecular mechanisms of therapeutic resistance and develop more effective novel treatment strategies, and further to reaching better clinical outcomes of patients with neuroblastoma."

Late-breaking abstract