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  • ||||||||||  Journal:  GATOR1 Mutations Impair PI3 Kinase-Dependent Growth Factor Signaling Regulation of mTORC1. (Pubmed Central) -  Feb 28, 2024   
    In the absence of the GATOR1 complex, cells are refractory to PI3K-dependent inhibition of mTORC1, permitting sustained translation and restricting the nuclear localization of TFEB, a transcription factor regulated by mTORC1. Collectively, our results show that epilepsy-linked mutations in NPRL2 can block GATOR1 complex assembly and restrict the appropriate regulation of mTORC1 by canonical PI3K-dependent growth factor signaling in the presence or absence of amino acids.
  • ||||||||||  Review, Journal:  Molecular Targeting of the Phosphoinositide-3-Protein Kinase (PI3K) Pathway across Various Cancers. (Pubmed Central) -  Feb 28, 2024   
    However, the limited clinical efficacy of these inhibitors, intolerable toxicities, and acquired resistances limit the clinical application of PI3K inhibitors. This review discusses the PI3K signaling pathway, alterations in the PI3K pathway causing carcinogenesis, current and novel PI3K pathway inhibitors, adverse effects, resistance mechanisms, challenging issues, and future directions of PI3K pathway inhibitors.
  • ||||||||||  Piqray (alpelisib) / Novartis
    401-B - Clinical Pearl 2: Best Practices  (Ballroom A) -  Feb 27, 2024 - Abstract #HOPA2024HOPA_94;    
    Session Description: The PI3K inhibitor alpelisib, indicated in PI3KC-mutated, hormone positive advanced breast cancer, has a known incidence of hyperglycemia in up to 79% of patients, with up to 39% of patients experiencing grade 3-4 hyperglycemia. Timely identification and proper management of hyperglycemia is critical to maintain treatment consistency and safety.This session will review alpelisib-induced hyperglycemia, prevention methods, hyperglycemia evaluation considerations, and management strategies to reduce treatment interruptions and discontinuations.Learning Objectives:
  • ||||||||||  colchicine / Generic mfg.
    Journal:  Transcriptional regulation of SARS-CoV-2 receptor ACE2 by SP1. (Pubmed Central) -  Feb 24, 2024   
    In Syrian hamsters (Mesocricetus auratus) infected with SARS-CoV-2, inhibition of SP1 by either mithramycin A or colchicine resulted in reduced viral replication and tissue injury. In summary, our study uncovers a novel function of SP1 in the regulation of ACE2 expression and identifies SP1 as a potential target to reduce SARS-CoV-2 infection.
  • ||||||||||  LY294002 / Eli Lilly
    Preclinical, Journal:  Antidiabetic Effect of Urolithin A in Cultured L6 Myotubes and Type 2 Diabetic Model KK-Ay/Ta Mice with Glucose Intolerance. (Pubmed Central) -  Feb 23, 2024   
    This elevation in GU by UroA treatment was partially inhibited by the concurrent addition of LY294002, an inhibitor of phosphatidylinositol 3-kinase (PI3K) which activates Akt (PKB: protein kinase B) or Compound C, an inhibitor of 5'-adenosine monophosphate-activated protein kinase (AMPK)...UroA was demonstrated to alleviate glucose intolerance. These results suggest that UroA is a biofactor with antihyperglycemic effects in the T2D state.
  • ||||||||||  LY294002 / Eli Lilly
    Journal:  YTHDF2-regulated matrilin-3 mitigates post-reperfusion hemorrhagic transformation in ischemic stroke via the PI3K/AKT pathway. (Pubmed Central) -  Feb 22, 2024   
    YTHDF2 knockdown inactivated the PI3K/AKT pathway, inhibited inflammation and decreased blood-brain barrier-related protein levels in cells; these effects were reversed by matrilin-3 deficiency. These results indicate that YTHDF2-regulated matrilin-3 protected ischemic rats against post-reperfusion hemorrhagic transformation via the PI3K/AKT pathway and that matrilin may have therapeutic potential in ischemic stroke.
  • ||||||||||  Journal:  Genetic loss of Nrf1 and Nrf2 leads to distinct metabolism reprogramming of HepG2 cells by opposing regulation of the PI3K-AKT-mTOR signalling pathway. (Pubmed Central) -  Feb 21, 2024   
    Further experiments revealed that such distinctive metabolic programming of between Nrf1?-/- and Nrf2-/- resulted from substantial activation of the PI3K-AKT-mTOR signalling pathway upon the loss of Nrf1, leading to increased expression of critical genes for the glucose uptake, glycolysis, the pentose phosphate pathway, and the de novo lipid synthesis, whereas deficiency of Nrf2 resulted in the opposite phenomenon by inhibiting the PI3K-AKT-mTOR pathway. Altogether, these provide a novel insight into the cancer metabolic reprogramming and guide the exploration of a new strategy for targeted cancer therapy.
  • ||||||||||  Piqray (alpelisib) / Novartis
    Journal, Tumor cell:  Concomitant inhibition of PI3K/mTOR signaling pathways boosts antiproliferative effects of lanreotide in bronchopulmonary neuroendocrine tumor cells. (Pubmed Central) -  Feb 20, 2024   
    We focused on assessing whether pretreating cells with inhibitors for phosphatidylinositol 3-kinase (PI3K) and mammalian target for rapamycin (mTOR) could enhance the antiproliferative effects of lanreotide...Additionally, combination treatment consisting of BYL719 and everolimus plus lanreotide tested in NCI-H720 and NCI-H727 led to diminished cell proliferation in a dose-dependent manner...Interestingly, SSTR expression reinduction could be exploited in therapeutic and diagnostic applications. The overall results of this study support the evaluation of combination-based therapies using lanreotide in preclinical studies to further increase its antiproliferative effect and ultimately facilitate its use in high-grade tumors.
  • ||||||||||  LY294002 / Eli Lilly
    Journal:  Targeting scleral remodeling and myopia development in form deprivation myopia through inhibition of EFEMP1 expression. (Pubmed Central) -  Feb 20, 2024   
    Validation was performed using lentivirus-induced overexpression and shRNA targeting EFEMP1 in combination with LY294002, a PI3K inhibitor...In contrast, the AAV-mediated overexpression of EFEMP1 exacerbated the development of myopia and resulted in further thinning of collagen fibers in the posterior sclera. In summary, adjusting EFEMP1 concentrations could potentially serve as a viable approach to prevent and treat myopia by influencing the remodeling process of the posterior sclera.
  • ||||||||||  RLY-5836 / Relay Therap
    Enrollment closed, Trial completion date, Trial primary completion date, Combination therapy, Metastases:  First-in-Human Study of RLY-5836 in Advanced Breast Cancer and Other Solid Tumors (clinicaltrials.gov) -  Feb 20, 2024   
    P1,  N=265, Active, not recruiting, 
    In summary, adjusting EFEMP1 concentrations could potentially serve as a viable approach to prevent and treat myopia by influencing the remodeling process of the posterior sclera. Recruiting --> Active, not recruiting | Trial completion date: Jan 2026 --> Jul 2024 | Trial primary completion date: Dec 2025 --> Jun 2024
  • ||||||||||  LY294002 / Eli Lilly, picropodophyllin (AXL1717) / Axelar
    Preclinical, Journal:  Suppression of overactive IGF-1 attenuates trauma-induced heterotopic ossification in mice. (Pubmed Central) -  Feb 19, 2024   
    Inhibitors of PI3K (LY294002) and mTOR (Rapamycin) both suppressed the IGF-1-stimulated mTOR signal and mitigated the formation of ectopic bones significantly. In conclusion, our results indicated that IGF-1 mediated the progression of traumatic HO through PI3K/Akt/mTOR signaling, and suppressing IGF-1 signaling cascades attenuated HO formation, providing a promising therapeutic strategy targeting HO.
  • ||||||||||  Journal:  Metabolic rewiring and autophagy inhibition correct lysosomal storage disease in mucopolysaccharidosis IIIB. (Pubmed Central) -  Feb 16, 2024   
    Indeed, metabolomic analyses revealed defects of mitochondrial activity accompanied by anaerobic metabolism and inhibition of AMP-activated protein kinase (AMPK), which acts on metabolism and autophagy, rescues lysosomal defects. These results provide insights into the molecular mechanisms of MPS IIIB physiopathology, supporting the development of new promising approaches based on autophagy inhibition and metabolic rewiring to correct lysosomal pathology in MPSs.
  • ||||||||||  Imbruvica (ibrutinib) / AbbVie, J&J
    Preclinical, Journal:  Ibrutinib-induced pulmonary angiotensin-converting enzyme activation promotes atrial fibrillation in rats. (Pubmed Central) -  Feb 15, 2024   
    Importantly, we observed that perindopril significantly mitigated ibrutinib-induced left atrial remodeling and AF promotion by inhibiting the activation of the ACE and its downstream CSK-Src signaling pathway. These findings indicate that the Ibrutinib-induced activation of the ACE contributes to AF development and could serve as a novel target for potential prevention strategies.
  • ||||||||||  Journal:  The Potential of PIP3 in Enhancing Wound Healing. (Pubmed Central) -  Feb 14, 2024   
    Free PIP3 and the Q-starch/PIP3 complexes inherently activated the AKT signaling pathway, which is responsible for crucial wound healing processes such as migration; this was also observed in wound assays in mice. PIP3 was identified as a promising molecule for enhancing wound healing, and its ability to circumvent PI3K inhibition suggests possible implications for chronic wound healing.
  • ||||||||||  Journal:  Antiplatelet effects of the CEACAM1-derived peptide QDTT. (Pubmed Central) -  Feb 12, 2024   
    QDTT also suppressed platelet secretion and "inside-out" GP IIb/IIIa activation by convulxin, along with inhibiting PI3K/Akt pathways. QDTT curtailed FeCl3-induced mesenteric thrombosis without significantly prolonging bleeding time, implying the potential of CEACAM1 A1 domain against platelet activation without raising bleeding risk, thus paving the way for novel antiplatelet drugs.
  • ||||||||||  Piqray (alpelisib) / Novartis, RLY-2608 / Relay Therap
    Journal:  Allosteric PI3K-alpha inhibition overcomes on-target resistance to orthosteric inhibitors mediated by secondary PIK3CA mutations. (Pubmed Central) -  Feb 9, 2024   
    PIK3CA mutations occur in ?8% of cancers, including ?40% of HR-positive breast cancers, where the PI3K-alpha (PI3K?)-selective inhibitor alpelisib is FDA approved in combination with fulvestrant...Some mutations had differential effects on PI3K?-selective versus pan-PI3K inhibitors, but resistance induced by all mutations could be overcome by the novel allosteric pan-mutant-selective PI3K?-inhibitor RLY-2608...Some mutations had differential effects on PI3Ka-selective vs. pan-PI3K inhibitors, but resistance induced by all mutations could be overcome by the novel allosteric pan-mutant-selective PI3Ka-inhibitor RLY-2608. Together, these findings provide insights to guide strategies to overcome resistance in PIK3CA-mutated cancers.
  • ||||||||||  Review, Journal, Tumor mutational burden, PD(L)-1 Biomarker, IO biomarker, Synthetic lethality:  Therapeutic Role of Synthetic Lethality in ARID1A-Deficient Malignancies. (Pubmed Central) -  Feb 8, 2024   
    As ARID1A deficiency correlates with enhanced tumor mutability, microsatellite instability, high tumor mutation burden, increased programmed death-ligand 1 expression, and T-lymphocyte infiltration, ARID1A-deficient cells can be a potential therapeutic target for immune checkpoint inhibitors that warrants further exploration. In this review, we discuss the role of ARID1A in carcinogenesis, its crosstalk with other signaling pathways, and strategies to make ARID1A-deficient cells a potential therapeutic target for patients with cancer.
  • ||||||||||  Journal:  ?1 integrin mediates unresponsiveness to PI3K? inhibition for radiochemosensitization of 3D HNSCC models. (Pubmed Central) -  Feb 8, 2024   
    Finally, we demonstrate that targeting of the cell adhesion molecule ?1 integrin on top of Alpelisib sensitizes non-responders to radiochemotherapy. Taken together, our study demonstrates the sensitizing potential of Alpelisib and other PI3K inhibitors in HNSCC models and uncovers a novel ?1 integrin-dependent mechanism that may prove useful in overcoming resistance to PI3K inhibitors.