pan-AKT inhib 
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  • ||||||||||  capivasertib (AZD5363) / Otsuka, AstraZeneca
    Preclinical efficacy of abiraterone plus capivasertib in mouse Pten-deficient prostate cancer (E-Poster Website) -  Mar 9, 2022 - Abstract #AACR2022AACR_6749;    
    Additionally, mice treated with combination therapy also had enrichments in genes sets associated to T cell, NK cell and as well as T cell activation, cytotoxicity, and interferon gamma signature. The findings from this study provide preclinical evidence for the efficacy of combination therapy with abiraterone plus capivasertib and provides insights into its immunomodulatory effects and influence on antitumor immunity.
  • ||||||||||  abiraterone acetate / Generic mfg.
    Journal, PARP Biomarker:  Inside prostate cancer news from the 2021 ASCO Genitourinary Cancers Symposium. (Pubmed Central) -  Mar 4, 2022   
    Loss of PTEN could be a target for ipatasertib (a pan-AKT inhibitor) associated with abiraterone in mCRPC patients. The 2021 ASCO Genitourinary Cancers Symposium significantly contributed to the complex research goal of intimately understanding PC carcinogenesis with the ultimate aim of improving patient outcomes.
  • ||||||||||  ipatasertib (RG7440) / Roche
    Clinical, PK/PD data, Journal:  Pharmacokinetics of Ipatasertib in Subjects With Hepatic Impairment Using Two Methods of Classification of Hepatic Function. (Pubmed Central) -  Mar 1, 2022   
    Based upon the results from this study, no dosage adjustment is required for ipatasertib when treating patients with mild hepatic impairment, whereas a dose reduction would be recommended for subjects with moderate or severe hepatic impairment. Based on real world data analysis, ?2% of intended patient population is expected to need a modified dose due to moderate or severe hepatic impairment.
  • ||||||||||  Journal, Nanostring, PARP Biomarker:  NanoString Digital Molecular Profiling of Protein and microRNA in Rhabdomyosarcoma. (Pubmed Central) -  Feb 16, 2022   
    This study highlights the utility of NanoString digital profiling methods in RMS, where it can detect distinct molecular signatures with the expression of signaling pathways and microRNAs from FFPE tumor tissue that may help identify prognostic biomarkers of interest. The overexpression of INPP4B and miR-3144-3p, miR-612, miR-302d-3p, miR-421, miR-548y and miR-548ar-5p may be associated with worse overall survival in ERMS and SRMS.
  • ||||||||||  miransertib (MK-7075) / Merck (MSD)
    Clinical, Journal:  Case Report: Five-Year Experience of AKT Inhibition with Miransertib (MK-7075) in an Individual with Proteus Syndrome. (Pubmed Central) -  Jan 13, 2022   
    It shows that at the doses used, miransertib has a favorable safety profile and durable benefit of improving symptoms of pain and slowing progression of overgrowth in Proteus syndrome in a single individual. While an uncontrolled single report cannot prove safety or efficacy, these data lend support to the encouraging preliminary data of our prior phase 1 pharmacodynamic study.
  • ||||||||||  ipatasertib (GDC-0068) / Roche
    Clinical, Journal:  Evaluation of Ipatasertib Interactions with Itraconazole and Coproporphyrin I and III in a Single Drug Interaction Study in Healthy Subjects. (Pubmed Central) -  Dec 25, 2021   
    Significance Statement In this drug-drug interaction study in healthy volunteers, we demonstrated that CYP3A4 plays a major role in ipatasertib clearance, and that ipatasertib is not an OATP1B1/1B3 inhibitor. Furthermore, it was demonstrated that itraconazole, an inhibitor of CYP3A4 and several transporters did not affect CPI/CPIII levels in vivo This increases the understanding and application of these endogenous substrates as well as itraconazole in complex drug interaction studies.
  • ||||||||||  Journal:  Akt isoforms differentially provide for chemoresistance in prostate cancer. (Pubmed Central) -  Oct 1, 2021   
    E-cadherin-induced activation of Akt1/2 isoforms was the essential mechanism of chemoresistance, whereas Akt3 made cells more fragile. These findings emphasized the need to target Akt1/2, rather than pan-Akt, as a rational therapeutic approach.
  • ||||||||||  Jevtana (cabazitaxel) / Sanofi, Emcure
    Preclinical, Journal:  Akt Inhibition Improves the Efficacy of Cabazitaxel Nanomedicine in Preclinical Taxane-Resistant Cancer Models. (Pubmed Central) -  Sep 24, 2021   
    Cabazitaxel has shown the ability to overcome drug resistance induced by paclitaxel and docetaxel; however, substantially high toxicity has been observed in patients receiving this agent, which compromises its efficacy...We therefore hypothesized that combing cabazitaxel nanotherapeutics with a pan-Akt inhibitor MK-2206 would synergistically sensitize the resistant cancer...Mechanistically, Akt inhibition increased the microtubule-stabilizing effect of cabazitaxel nanomedicine. Collectively, this report introduced a binary platform composed of cytotoxic nanotherapeutics and inhibitors with certain targets to combat multidrug resistance, and such a combined regimen has the potential for the clinical treatment of patients with resistant cancer.
  • ||||||||||  Erleada (apalutamide) / J&J
    Preclinical, Journal:  Context-Specific Efficacy of Apalutamide Therapy in Preclinical Models of Pten-Deficient Prostate Cancer. (Pubmed Central) -  Aug 28, 2021   
    Upregulation of signal transducer and activator of transcription 3 (STAT3) and proviral insertion in murine-1 (PIM-1) were associated with combined apalutamide/GSK690693. Our findings show that apalutamide can attenuate Pten-deficient PCa in a context-specific manner and provides data that can be used to further study and, possibly, develop additional combinations with apalutamide.
  • ||||||||||  Review, Journal:  Molecular target: pan-AKT in gastric cancer. (Pubmed Central) -  Aug 20, 2021   
    Accordingly, as an attractive therapeutic target for cancer treatment, several AKT inhibitors are currently under development and in multiple stages of clinical trials for various types of malignancy, including gastric cancer (GC). Therefore, the authors review the significance of AKT and recent studies on AKT inhibitors in GC, focusing on the scientific background with the potential to improve treatment outcomes.
  • ||||||||||  imatinib / Generic mfg.
    Journal:  Combined Inhibition of AKT and KIT Restores Expression of Programmed Cell Death 4 (PDCD4) in Gastrointestinal Stromal Tumor. (Pubmed Central) -  Aug 8, 2021   
    The majority of gastrointestinal stromal tumor (GIST) patients develop resistance to the first-line KIT inhibitor, imatinib mesylate (IM), through acquisition of secondary mutations in KIT or bypass signaling pathway activation...We evaluated the activity of a novel pan-AKT inhibitor, MK-4440 (formerly ARQ 751), as monotherapy and in combination with IM in GIST cell lines and preclinical models with varying IM sensitivities...The combination demonstrated limited efficacy in two IM-resistant models, including a GIST patient-derived xenograft model possessing an exon 9 KIT mutation. These studies provide strong rationale for further use of AKT inhibition in combination with IM in primary GIST; however, alternative agents will need to be tested in combination with AKT inhibition in the resistant setting.
  • ||||||||||  progesterone / Generic mfg.
    Journal:  Alterations in the insulin signaling pathway in bovine ovaries with experimentally induced follicular persistence. (Pubmed Central) -  Jun 22, 2021   
    Thus, the aim of this study was to examine the expression of critical nodes of the insulin pathway, including insulin receptor (IR), IR substrate (IRS), phosphatidylinositol-3-kinase (PI3K), and protein kinase B (also known as Akt or pan-Akt), in ovarian follicular structures of cows during the development of follicular persistence induced by long-term progesterone administration...Serum and follicular fluid insulin concentration was higher in cows with persistent follicles than in control cows. These results show that decreased expression and/or activation of the receptors and other intermediates of the insulin signaling pathway in persistent follicles indicates that reduced response/resistance to insulin rather than the concentration of insulin per se may be one of the important molecular mechanisms in the development of persistent follicles in dairy cows.
  • ||||||||||  miransertib (MK-7075) / Merck (MSD)
    Clinical, Journal:  Clinical experience with the AKT1 inhibitor miransertib in two children with PIK3CA-related overgrowth syndrome. (Pubmed Central) -  Jun 22, 2021   
    P1/2
    This case series highlights the potential therapeutic utility of miransertib in selected paediatric patients with severe PROS, and further demonstrates the potential for re-purposing targeted therapies for the treatment of rare diseases. An open label, Phase 1/2 study of miransertib in children with PROS and PS is underway to more accurately assess the efficacy of miransertib in the treatment of PROS disorder (NCT03094832).
  • ||||||||||  capivasertib (AZD5363) / Otsuka, AstraZeneca
    Biomarker, Journal:  Assessment of PI3K/mTOR/AKT Pathway Elements to Serve as Biomarkers and Therapeutic Targets in Penile Cancer. (Pubmed Central) -  Jun 3, 2021   
    Treatment with pan-AKT inhibitor capivasertib in PeCa cell lines induced a significant downregulation of both total AKT and pAKT as well as decreased cell viability and chemotaxis. Selected protein candidates of the mTOR/AKT signaling pathway demonstrate association with histological and survival parameters of PeCa patients, whereas AKT appears to be the most promising one.
  • ||||||||||  dipyridamole / Generic mfg.
    Preclinical, Journal:  Metabolic Interventions to Prevent Hypertrophy-Induced Alterations in Contractile Properties In Vitro. (Pubmed Central) -  May 14, 2021   
    Importantly, the increased glucose uptake preceded structural and functional changes, suggesting a causal role for metabolism in the onset of PE-induced hypertrophy. Indeed, PE treatment in the presence of a PAN-Akt inhibitor or of a GLUT4 inhibitor dipyridamole prevented PE-induced increases in cellular glucose uptake and ameliorated PE-induced contractile alterations; (4) Pharmacological interventions, forcing substrate metabolism away from glucose utilization, improved contractile properties in PE-treated cardiomyocytes, suggesting that targeting glucose uptake, independent from protein synthesis, forms a promising strategy to prevent hypertrophy and hypertrophy-induced cardiac dysfunction.
  • ||||||||||  Journal:  AKT Inhibitors: The Road Ahead to Computational Modeling-Guided Discovery. (Pubmed Central) -  May 14, 2021   
    Finally, results of molecular dynamics simulations were used to estimate the theoretical binding affinity of the selected virtual hits towards the three isoforms of enzyme AKT. Our computational findings thus provide important guidelines to facilitate the discovery of novel AKT inhibitors.
  • ||||||||||  Nexavar (sorafenib) / Bayer, Amgen
    [VIRTUAL] AKT KINASE REGULATES TIM-3 EXPRESSION IN MYELOID NEOPLASMS () -  May 13, 2021 - Abstract #EHA2021EHA_1607;    
    Conclusion A promising direction for further research in AML and MDS is not only blockage of TIM3 signaling by monoclonal antibodies, but also elucidation of pathways leading to TIM3 expression on malignant cells. Further research is required to identify the mechanisms of Akt-mediated TIM3 downregulation.
  • ||||||||||  ipatasertib (GDC-0068) / Roche
    Journal:  Imperatorin promotes osteogenesis and suppresses osteoclast by activating AKT/GSK3 β/β-catenin pathways. (Pubmed Central) -  Apr 28, 2021   
    We used ipatasertib, a pan-AKT inhibitor, to inhibit the osteogenic effect of imperatorin, and found that imperatorin promotes osteogenesis via AKT/GSK3β/β-catenin pathway...Intragastric administration of imperatorin promoted osteogenesis and inhibited osteoclast in vivo. Our experiments showed that imperatorin is a potential drug for osteoporosis treatment.
  • ||||||||||  Revlimid (lenalidomide) / BMS
    Journal:  Discovery of an AKT Degrader with Prolonged Inhibition of Downstream Signaling. (Pubmed Central) -  Mar 16, 2021   
    Notably, INY-03-041 promoted sustained AKT degradation and inhibition of downstream signaling effects for up to 96 h, even after compound washout. Our findings suggest that AKT degradation may confer prolonged pharmacological effects compared with inhibition, and highlight the potential advantages of AKT-targeted degradation.
  • ||||||||||  capivasertib (AZD5363) / Otsuka, AstraZeneca
    Journal:  Targeting castration-resistant prostate cancer with androgen receptor antisense oligonucleotide therapy. (Pubmed Central) -  Oct 7, 2020   
    This treatment strategy effectively improved treatment responses and prolonged survival in a clinically relevant mouse model of advanced CRPC. Thus, our data provide preclinical evidence to support a combination strategy of next-generation ASOs targeting AR in combination with AKT inhibition as a potentially beneficial treatment approach for CRPC.
  • ||||||||||  fulvestrant / Generic mfg.
    [VIRTUAL] Detection of PI3K pathway activation in circulating tumor cells in PIK3CA mutated metastatic breast cancer as a putative predictive biomarker for PI3K inhibitor therapies (OnDemand) -  Oct 2, 2020 - Abstract #SABCS2020SABCS_411;    
    Future work will prospectively evaluate multiple clinical applications of this assay in patients receiving alpelisib plus endocrine therapy for PIK3CA mutated HR+ metastatic breast cancer, as well as expanding the assay to include the detection of additional phospho-protein readouts of PI3K pathway activity in CTCs. In addition to the potential to complement solid biopsy PIK3CA mutation status as a predictive biomarker of sensitivity to PI3K therapies, this assay has the unique potential to provide a pharmacodynamic assessment of PI3K inhibitor activity in CTCs while on treatment, which may serve as an early biomarker of clinical response or resistance.
  • ||||||||||  miransertib (MK-7075) / Merck (MSD), sirolimus / Generic mfg.
    [VIRTUAL] Miransertib treatment of PIK3CA‐related overgrowth syndrome: a paediatric case series () -  Sep 9, 2020 - Abstract #BAD2020BAD_196;    
    P1/2
    Thus, we report the first paediatric case series of the use of miransertib in two children with PROS. An open‐label, phase I/II study of miransertib in children with PROS and PS is currently underway to more accurately assess the efficacy of miransertib in the treatment of PIK3CA‐related overgrowth disorder (NCT03094832).