danusertib (PHA-739358) / Nerviano Medical Sciences 
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 18 Diseases   0 Trials   0 Trials   62 News 
  • ||||||||||  danusertib (PHA-739358) / Nerviano Medical Sciences
    Journal:  Suppression of NSCLC progression via the co-administration of Danusertib, an AURK inhibitor, and KRIBB11, an HSF1 inhibitor. (Pubmed Central) -  Apr 22, 2024   
    Furthermore, the combination treatment inhibits tumor growth and AKT signaling in the xenograft mouse model, increases levels of the tumor tissue oxidation product malondialdehyde (MDA), and induces DNA damage. To summarize, a potential therapeutic approach for NSCLC may involve dual inhibition of AURK and HSF1, resulting in the downregulation of the PI3K/AKT signaling pathway, and the activation of ROS-mediated mitochondrial and DNA damage pathways.
  • ||||||||||  berzosertib (M6620) / EMD Serono, danusertib (PHA-739358) / Nerviano Medical Sciences
    Molecular correlates of drug response to guide therapy in triple-negative breast cancer (Hall 2-3) -  Nov 4, 2023 - Abstract #SABCS2023SABCS_911;    
    Furthermore, combining the pan-AK inhibitor danusertib with berzosertib results in synergistic killing of TNBC cells. As a future direction, we are evaluating this combination in vivo utilizing an ethnically diverse patient-derived xenograft library grown in mice to evaluate this novel combination in a mock clinical trial and to identify molecular correlates of response and resistance that could be used to guide future human trials.
  • ||||||||||  danusertib (PHA-739358) / Nerviano Medical Sciences, alisertib (MLN8237) / Puma, ABT-737 / AbbVie
    Journal:  Combined inhibition of Aurora Kinases and Bcl-xL induces apoptosis through select BH3-only proteins. (Pubmed Central) -  Feb 27, 2023   
    On the other hand, we found Alisertib treatment causes activation of caspase-2, which promotes apoptosis by cleaving Bid into tBid, a suppressor of both Bcl-xL and Mcl-1. Together, these results define the Bcl-2 protein network critically involved in AURK inhibitor-induced apoptosis, and suggest that BH3-mimetics targeting Bcl-xL may help overcome resistance to AURK inhibitors in cancer cells.
  • ||||||||||  Journal:  Forecasting Gastric Cancer Diagnosis, Prognosis, and Drug Repurposing with Novel Gene Expression Signatures. (Pubmed Central) -  May 11, 2022   
    Through text mining analysis and literature search validation, Belinostat and Danusertib were suggested as possible novel drug candidates for GC treatment. These findings collectively inform multiple aspects of GC medical management, including its precision diagnosis, forecasting of possible outcomes, and drug repurposing for innovation in GC medicines in the future.
  • ||||||||||  Aurora kinase B expression shields HNSCC from PI3K inhibition-induced apoptosis through downstream mediators AKT and PDK1 (Section 22) -  Mar 9, 2022 - Abstract #AACR2022AACR_5350;    
    To use a pharmacologic approach, we combined the pan-Aurora kinase inhibitor danusertib (0-2µM) with PI3K/mTOR inhibitor omipalisib (0-200nM) in 56 HNSCC cell lines for 72h and observed a substantial decrease in cell viability in >80% of NOTCH1WT and >90% of NOTCH1MUT HNSCC lines...Mice bearing NOTCH1MUT xenografts showed complete tumor regression when treated with a combination of pan-PI3K inhibitor Copanlisib and Aurora inhibitor Alisertib as compared to control groups...We identified AURKB as a central player governing the sensitivity to PI3K inhibitor-induced apoptosis in the context of NOTCH1 mutation status in HNSCC through its effects on AKT and PDK1. These novel findings may lead to the development of more robust therapeutic approach for NOTCH1 mutant squamous carcinoma as well as patients who develop acquired resistance to targeted therapies.
  • ||||||||||  Journal:  Combined Inhibition of Polo-Like Kinase-1 and Wee1 as a New Therapeutic Strategy to Induce Apoptotic Cell Death in Neoplastic Mast Cells. (Pubmed Central) -  Feb 16, 2022   
    Wee1 inhibition by MK1775 after 24 h treatment with danusertib or volasertib, when cells were arrested in G2 phase and Wee1, was overexpressed and hyper-activated, resulting in a significantly higher rate of apoptosis than that obtained from concomitant treatment with danusertib or volasertib + MK1775 for 48 h. In conclusion, Plk1 and AKA, alone or together with Wee1, are attractive therapeutic targets in neoplastic MCs. Repurposing Plk1 or AKA ± Wee1 inhibitors in advanced clinical development for other indications is a therapeutic strategy worthy of being explored, in order to improve the outcome of patients with advanced SM.
  • ||||||||||  danusertib (PHA-739358) / Nerviano Medical Sciences
    Journal:  Augmentation of danusertib's anticancer activity against melanoma by blockage of autophagy. (Pubmed Central) -  Oct 7, 2020   
    Thus, the induction of autophagy by danusertib appears to be a survival mechanism in melanoma cells that may counteract its anticancer effects. These findings suggest a novel strategy to enhance the anticancer efficacy of danusertib in melanoma by blocking autophagy.
  • ||||||||||  danusertib (PHA-739358) / Nerviano Medical Sciences, buparlisib (BKM120) / Novartis, Adlai Nortye
    Preclinical, Journal:  ERK-dependent IL-6 positive feedback loop mediates resistance against a combined treatment using danusertib and BKM120 in Burkitt lymphoma cell lines. (Pubmed Central) -  Aug 19, 2020   
    A blockade of ERK signaling with trametinib suppressed the combination treatment-induced ERK activation, reduced IL-6 mRNA expression, and downregulated IL-6R mRNA expression, resulting in an improvement in the antitumor effect. We stepwise treated Namalwa cells with both inhibitors using on-and-off treatment cycles and found that Namalwa cells gained chemoresistance by activating the ERK/IL-6 feedback loop, suggesting that the ERK-dependent IL-6 positive feedback loop can compensate for AKT inactivation and is closely associated with adaptive resistance and relapse.
  • ||||||||||  omipalisib (GSK2126458) / GSK, danusertib (PHA-739358) / Nerviano Medical Sciences
    Aurora kinases mediate resistance to PI3K inhibition in head and neck squamous cell carcinoma (The Westin Kierland Resort and Spa) -  Feb 27, 2020 - Abstract #MHNCS2020MHNCS_247;    
    P2
    To the best of our knowledge, this is the first study to identify Aurora kinases as a mechanism of resistance to PI3K inhibition in any cancer type. The finding that the combination of PI3K and Aurora kinase inhibition led to synergy in both NOTCH1 mutant and wt HNSCC suggests that this combination will be broadly effective in HNSCC patients who may have heterogeneous tumors.
  • ||||||||||  JQ-1 / Roche, danusertib (PHA-739358) / Nerviano Medical Sciences, Farydak (panobinostat) / Novartis
    Journal:  Inhibitors of Signaling Pathways that Block Reversal of HIV-1 Latency. (Pubmed Central) -  Jan 29, 2020   
    Both danusertib and PF-3758309 inhibited latency reversal in CD4+ T cells isolated from HIV-1-infected donors. Collectively, our study describes a chemical approach that can be applied to elucidate the role of signaling pathways involved in LRA activity, or the maintenance of HIV-1 latency; and also identifies inhibitors of latent HIV-1 reactivation that could be used with antiretroviral therapy to reduce residual viremia.
  • ||||||||||  imatinib / Generic Mfg., danusertib (PHA-739358) / Nerviano Medical Sciences, volasertib (BI 6727) / Boehringer Ingelheim
    Journal:  Hyper-activation of Aurora kinase a-polo-like kinase 1-FOXM1 axis promotes chronic myeloid leukemia resistance to tyrosine kinase inhibitors. (Pubmed Central) -  Nov 27, 2019   
    Collectively, our study describes a chemical approach that can be applied to elucidate the role of signaling pathways involved in LRA activity, or the maintenance of HIV-1 latency; and also identifies inhibitors of latent HIV-1 reactivation that could be used with antiretroviral therapy to reduce residual viremia. Our conclusion is that AURKA, PLK1 and FOXM1 inhibition may be considered as a promising therapeutic approach to cure CML.
  • ||||||||||  Rydapt (midostaurin) / Novartis
    In Systemic Masocytosis, Midostaurin Targets Both Kit and Aurora Kinase a Reverting H3K36Me3 Deficiency and Synergizes with Second-Generation Tyrosine Kinase Inhibitors (Hall B, Level 2 (Orange County Convention Center)) -  Nov 7, 2019 - Abstract #ASH2019ASH_5945;    
    Both pharmacological inhibition by Danusertib and siRNA-mediated knock-down of AKA rescued SETD2 expression and activity, raising the hypothesis that phosphorylation by AKA might be implicated in proteasome-mediated degradation of SETD2...We performed growth curves in liquid medium and clonogenic assays to evaluate the therapeutic potential of pharmacological combination of midostaurin with Nilotinib and Dasatinib in HMC-1 cells and in neoplastic mast cells from 3 patients with advSM and we observed in all cases synergistic effects at nanomolar doses...Inhibiting AKA and c-Kit activity by midostaurin in combination with a second generation TKI is a promising therapeutic strategy in patients with SETD2/H3K36Me3 deficiency . Acknowledgments: study supported by AIRC (project code 16996) and AIL (Associazione Italiana contro le Leucemia, Linfomi e Mieloma).
  • ||||||||||  Aurora Kinase a/MDM2-Mediated SETD2 Loss of Function in Chronic Myeloid Leukemia Patients in Blast Crisis Can be Therapeutically Targeted Inducing Apoptotic Cell Death in a Caspase-Dependent Way (Hall B, Level 2 (Orange County Convention Center)) -  Nov 7, 2019 - Abstract #ASH2019ASH_5880;    
    To investigate whether SETD2/H3K36Me3 loss may be a druggable lesion, we performed clonogenic assays in LAMA84 (SETD2/H3K36Me3high) cells before and after SETD2 silencing, in imatinib-sensitive K562 (SETD2/H3K36Me3low) cells and in IM-resistant K562 cells, that are characterized by complete SETD2 loss...Moreover, all drug treatments as single agent, at nanomolar doses (Bortezomib: 10 nM, Carfilzomib: 5 nM, Ixazomib: 10 nM and Danusertib: 500 nM) induced a significant increase of the DNA double-strand break marker γH2AX, suggesting that in a SETD2 knock-down context, proteasomal and AKA inhibition propagates genomic instability by forcing the cells through successive replication cycles, ultimately resulting in apoptosis from mitotic catastrophe...Restoring physiological H3K36Me3 may help to improve the outcome of this critical subset of pts. Acknowledgments: Study supported by AIRC (project code 16996), AIL (Associazione Italiana contro le Leucemia, Linfomi e Mieloma), Italian Ministry of Health, project GR-2016-02364880.
  • ||||||||||  Clinical, Review, Journal:  Past, present, and future of Bcr-Abl inhibitors: from chemical development to clinical efficacy. (Pubmed Central) -  Oct 29, 2019   
    Crystallographic and structure-activity relationship analysis, jointly to clinical data, were pivotal to shed light on this topic. More recently, preclinical evidence on bafetinib, rebastinib, tozasertib, danusertib, HG-7-85-01, GNF-2, and 1,3,4-thiadiazole derivatives lay promising foundations for better inhibitors to be approved for clinic in the near future.Notably, structural mechanisms of action and drug design exemplified by Bcr-Abl inhibitors have broad relevance to both break through resistances in CML treatment and develop inhibitors against other kinases as targeted chemotherapeutics.
  • ||||||||||  tozasertib (MK-0457) / Vertex, Merck (MSD)
    Journal:  RIPK1-dependent cell death: a novel target of the Aurora kinase inhibitor Tozasertib (VX-680). (Pubmed Central) -  Sep 18, 2019   
    The potency ranking of the newly derived Tozasertib analogues and their specificity profile, as observed in cellular assays, coincide with ADP-Glo recombinant kinase activity assays. Overall, we show that Tozasertib not only targets Aurora kinases but also RIPK1 independently, and that we could generate analogues with increased selectivity to RIPK1 or Aurora kinases, respectively.
  • ||||||||||  Afinitor (everolimus) / Novartis
    Journal:  The Osteogenic Niche Is a Calcium Reservoir of Bone Micrometastases and Confers Unexpected Therapeutic Vulnerability. (Pubmed Central) -  Aug 1, 2019   
    The Ca signaling, together with previously identified mammalian target of rapamycin signaling, promotes bone metastasis progression. Interestingly, effective inhibition of these pathways can be achieved by danusertib, or a combination of everolimus and arsenic trioxide, which provide possibilities of eliminating bone micrometastases using clinically established drugs.
  • ||||||||||  danusertib (PHA-739358) / Nerviano Medical Sciences, Lynparza (olaparib) / Merck (MSD), AstraZeneca
    Journal, BRCA Biomarker, PARP Biomarker:  Targeting the MYCN-PARP-DNA Damage Response Pathway inNeuroendocrine Prostate Cancer. (Pubmed Central) -  Jul 26, 2019   
    Targeting this pathway using in vitro and in vivo CRPC-Adeno and CRPC-Neuro models demonstrated a novel therapeutic strategy for NEPC. Further investigation of N-MYC-regulated DDR gene targets and the biological and clinical significance of MYCN-PARP-DDR signaling will more fully elucidate the importance of the MYCN-PARP-DDR signaling pathway in the development and maintenance of NEPC.