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  • ||||||||||  Venclexta (venetoclax) / Roche, AbbVie, SBI-756 - TGen, National Cancer Institute - Bethesda, Sanford / Burnham Medical Research Institute
    Journal:  Targeting eIF4F translation initiation complex with SBI-756 sensitises B lymphoma cells to venetoclax. (Pubmed Central) -  Sep 29, 2021   
    More generally, the resource generated by this work provides a foundation for establishing links between the MTOR-autophagy axis and proteins not previously linked to this pathway. Our data highlight a novel combination for treatment of aggressive lymphomas, and establishes its efficacy and selectivity using preclinical models.
  • ||||||||||  telaglenastat (CB-839) / Calithera
    Preclinical, Journal:  Reproducible Lipid Alterations in Patient-Derived Breast Cancer Xenograft FFPE Tissue Identified with MALDI MSI for Pre-Clinical and Clinical Application. (Pubmed Central) -  Sep 28, 2021   
    We evaluated technical reproducibility, spatial metabolic differentiation within tissue compartments, and treatment response induced by a glutaminase inhibitor (CB-839)...Moreover, this protocol identified distinct alterations in the tissue lipidome of xenograft treated with glutaminase inhibitors. In conclusion, lipidic alterations in FFPE tissue of breast cancer xenograft observed in this study are a step-forward to a robust and reproducible MALDI-MSI based workflow for pre-clinical and clinical applications.
  • ||||||||||  sapanisertib (TAK-228) / Takeda
    Journal:  Inhibition of NLRP3 Inflammasome Activation and Pyroptosis in Macrophages by Taraxasterol Is Associated With Its Regulation on mTOR Signaling. (Pubmed Central) -  Sep 19, 2021   
    Moreover, TAS treatment alleviated mitochondrial damage by nigericin and improved mouse survival from bacterial infection, accompanied by reduced IL-1β levels in vivo. Collectively, by inhibiting the NLRP3 inflammasome activation, TAS displayed anti-inflammatory effects likely through regulation of the mTOR signaling in macrophages, highlighting a potential action mechanism for the anti-inflammatory activity of Dandelion in treating inflammation-related disorders, which warrants further clinical investigation.
  • ||||||||||  cisplatin / Generic mfg.
    [VIRTUAL] SCREENING AND IDENTIFICATION OF NOVEL CHEMOTHERAPY AGENTS IN PLATINUM- RESISTANT OVARIAN CANCER () -  Aug 26, 2021 - Abstract #IGCS2021IGCS_493;    
    Neither telaglenastat, savolitinib, nor AMG-232 exhibit any appreciable cytotoxicity; however, mithramycin demonstrates cytotoxicity in the low nanomolar range in several representative ovarian cancer cell lines, including two platinum-resistant lines. The potential therapeutic benefit of mithramycin warrants further preclinical evaluation.
  • ||||||||||  telaglenastat (CB-839) / Calithera
    Journal:  Glutaminase inhibitors induce thiol-mediated oxidative stress and radio-sensitization in treatment resistant cervical cancers. (Pubmed Central) -  Aug 14, 2021   
    Glutamine dependent PI3K activated cervical cancer xenografts were sensitive to telaglenastat monotherapy, and telaglenastat selectively radio-sensitized cervical cancer cells in vitro and in vivo. These novel preclinical data support the utility of telaglenastat for glutamine dependent radio-resistant cervical cancers and demonstrate that PI3K pathway mutations may be used as a predictive biomarker for telaglenastat sensitivity.
  • ||||||||||  telaglenastat (CB-839) / Calithera
    Enrollment closed, Enrollment change, Trial completion date, Trial primary completion date, Combination therapy, Metastases:  A Study of Telaglenastat (CB-839) in Combination With Palbociclib in Patients With Solid Tumors (clinicaltrials.gov) -  Aug 11, 2021   
    P1b/2,  N=53, Active, not recruiting, 
    These novel preclinical data support the utility of telaglenastat for glutamine dependent radio-resistant cervical cancers and demonstrate that PI3K pathway mutations may be used as a predictive biomarker for telaglenastat sensitivity. Recruiting --> Active, not recruiting | N=85 --> 53 | Trial completion date: Jun 2021 --> Nov 2022 | Trial primary completion date: Jun 2020 --> Nov 2021
  • ||||||||||  Exkivity (mobocertinib) / Takeda
    [VIRTUAL] Targeting HER2 Exon 20–Mutant Lung Adenocarcinoma with a Novel Tyrosine Kinase Inhibitor, Mobocertinib (Program Auditorium) -  Aug 9, 2021 - Abstract #IASLCWCLC2021IASLC_WCLC_654;    
    Mobocertinib had the lowest HER2 exon 20 insertion IC50 / WT EGFR IC50 ratio of all three HER2 exon 20 insertion mutations compared with osimertinib, poziotinib, afatinib, neratinib, and pyrotinib, indicating that mobocertinib displayed the best selectivity profile in these models and could provide an improved efficacy and safety profile in clinic...We tested three drugs (alisertib, sapanisertib and T-DM1) for combination therapies...Conclusion We demonstrated that mobocertinib showed a robust inhibitory activity against HER2 exon 20 insertion mutations both in vitro and in vivo. Importantly, our study provides a strong rationale for further clinical trials using mobocertinib either alone or in combination with T-DM1 to target HER2-mutant lung cancer.
  • ||||||||||  doxorubicin hydrochloride / Generic mfg.
    Journal:  Compound 968 reverses adriamycin resistance in breast cancer MCF-7 cells via inhibiting P-glycoprotein function independently of glutaminase. (Pubmed Central) -  Aug 7, 2021   
    Furthermore, using drug affinity responsive target stability and streptavidin-biotin immunoprecipitation assays, we demonstrated that SY-1320 could specifically target P-glycoprotein (P-gp) and increase ADR accumulation through inhibition of P-gp, thereby resulting in cell death in MCF-7 cells. Together, our findings indicate that compound 968 or SY-1320 might be a promising drug for new combination chemotherapy in breast cancer to overcome the drug resistance.
  • ||||||||||  telaglenastat (CB-839) / Calithera
    Journal, IO biomarker:  Re-polarization of immunosuppressive macrophages to tumor-cytotoxic macrophages by repurposed metabolic drugs. (Pubmed Central) -  Aug 4, 2021   
    Our results show that by targeting cell metabolism, macrophages could be re-polarized from M2- into an anti-tumoral M1-like phenotype and that M0-to-M2 polarization could be prevented. Overall, this study provides rational for the use of clinically applicable drugs to change an immunosuppressive tumor environment into a pro-inflammatory tumor environment that could support cancer immunotherapies.
  • ||||||||||  telaglenastat (CB-839) / Calithera, Bylantra (devimistat) / Rafael Pharma, Ono Pharma
    [VIRTUAL] Therapeutic targeting of glutaminolysis and mitochondrial TCA cycle in head and neck cancer () -  Aug 3, 2021 - Abstract #AHNS2021AHNS_337;    
    Moreover, pharmacological blockade of the glutaminolysis pathway by GLS1 inhibitor CB-839 not only decreased cancer cell viability dependent on glutaminolysis, but also improved the therapeutic effectiveness of CPI-613 in cell culture and animal models. These findings provide novel evidence that alternative pathways of metabolism endowed cancer cells with metabolic stress, and suppressing the related compensatory pathways might achieve synergistic anticancer outcomes.
  • ||||||||||  Journal:  Assessment of the effects of Syk and BTK inhibitors on GPVI-mediated platelet signaling and function. (Pubmed Central) -  Jul 28, 2021   
    These inhibitors include four Syk inhibitors, Bay 61-3606, R406 (fostamatinib), entospletinib, TAK-659; four irreversible BTK inhibitors, ibrutinib, acalabrutinib, ONO-4059 (tirabrutinib), AVL-292 (spebrutinib); and four reversible BTK inhibitors, CG-806, BMS-935177, BMS-986195, and fenebrutinib...Similarly, these TKIs reduced the percentage of activated integrin αβ on the platelet surface in response to CRP-XL, as determined by PAC-1 binding...Select TKIs also inhibited platelet aggregate formation on collagen under physiological flow conditions. Together, our results suggest that TKIs targeting Syk or BTK inhibit central platelet functional responses but may differentially affect protein activities and organization in critical systems downstream of Syk and BTK in platelets.
  • ||||||||||  mivavotinib (CB-659) / Calithera
    Trial completion, Metastases:  A Study of TAK-659 in Adult Participants With Advanced Solid Tumor and Lymphoma Malignancies (clinicaltrials.gov) -  Jul 19, 2021   
    P1,  N=143, Completed, 
    Based on our data, HDAC inhibitors like Entinostat are synergistic with the ferroptosis-inducer Erastin and should be further advanced in preclinical models. Active, not recruiting --> Completed
  • ||||||||||  Journal:  Evolution of PIKK family kinase inhibitors: A new age cancer therapeutics. (Pubmed Central) -  Jul 14, 2021   
    Rapalogs, AZD8055, AZD2014, OSI-027, INK-128, MLN0128, VX970, NVP-BEZ235, Torin2, AZ20, and AZ31 are the diverse scaffolds which have successfully made into the pre-clinical trials either as mono or combinatorial therapy for the treatment of various human cancers. Their synthesis and pre-clinical trial highlight the challenges associated in the development process.
  • ||||||||||  sapanisertib (TAK-228) / Takeda
    Journal:  mTOR inhibitor INK128 promotes wound healing by regulating MDSCs. (Pubmed Central) -  Jul 10, 2021   
    Their synthesis and pre-clinical trial highlight the challenges associated in the development process. INK128 is potential to be developed as a clinical strategy to promote wound healing of diabetic patients.
  • ||||||||||  sapanisertib (TAK-228) / Takeda
    Clinical, P2 data, Clinical Trial,Phase II, Journal:  ANETT: PhAse II trial of NEoadjuvant TAK-228 plus Tamoxifen in patients with hormone receptor-positive breast cancer. (Pubmed Central) -  Jul 10, 2021   
    INK128 is potential to be developed as a clinical strategy to promote wound healing of diabetic patients. Tamoxifen and TAK-228 was safe and well tolerated neoadjuvant treatment for ER+ breast cancer, preliminary evidence of activity with significant reduction in both Ki-67 and tumor size, warranting further evaluation in a larger study.
  • ||||||||||  telaglenastat (CB-839) / Calithera
    Journal:  A facile and sensitive method of quantifying glutaminase binding to its inhibitor CB-839 in tissues. (Pubmed Central) -  Jul 7, 2021   
    Notably, we show that this assay detects CB-839 binding to glutaminase in platelets of patients collected while receiving CB-839 on a clinical trial. This assay may be used to study the pharmacodynamic profile of CB-839 in very small tissue samples obtained from patients on a clinical trial and may be useful in future studies designed to screen other inhibitors of glutaminase.
  • ||||||||||  Herceptin (trastuzumab) / Roche, sapanisertib (TAK-228) / Takeda
    Preclinical, Journal:  The Novel Oral mTORC1/2 Inhibitor TAK-228 Reverses Trastuzumab Resistance in HER2-Positive Breast Cancer Models. (Pubmed Central) -  Jul 4, 2021   
    Likewise, the combination of both drugs induced a significant increase in apoptosis. Collectively, these experiments support the combination of trastuzumab with PI3K/AKT/mTOR inhibitors as a potential strategy for inhibiting the proliferation of HER2-positive breast cancer cell lines that show resistance to trastuzumab.
  • ||||||||||  sapanisertib (CB-228) / Calithera
    Trial primary completion date:  Sapanisertib in Treating Patients With Locally Advanced or Metastatic Bladder Cancer With TSC1 and/or TSC2 Mutations (clinicaltrials.gov) -  Jul 2, 2021   
    P2,  N=209, Active, not recruiting, 
    Collectively, these experiments support the combination of trastuzumab with PI3K/AKT/mTOR inhibitors as a potential strategy for inhibiting the proliferation of HER2-positive breast cancer cell lines that show resistance to trastuzumab. Trial primary completion date: Jun 2021 --> Jun 2022
  • ||||||||||  telaglenastat (CB-839) / Calithera
    Journal:  Impaired anaplerosis is a major contributor to glycolysis inhibitor toxicity in glioma. (Pubmed Central) -  Jun 29, 2021   
    Together, these data suggest that at least for ENO1-deleted gliomas, tumors in vivo-unlike cells in culture-show limited dependence on glutaminolysis and instead primarily depend on glycolysis for anaplerosis. Our findings reinforce the previously reported metabolic idiosyncrasies of in vitro culture and suggest that cell culture media nutrient composition more faithful to the in vivo environment will more accurately predict in vivo efficacy of metabolism targeting drugs.
  • ||||||||||  mivavotinib (TAK-659) / Takeda
    Journal:  Novel potent and selective pyrazolylpyrimidine-based SYK inhibitors. (Pubmed Central) -  Jun 23, 2021   
    Hybridisation of amino-pyrimidine based SYK inhibitors (e.g. 1a) with previously reported diamine-based SYK inhibitors (e.g. TAK-659) led to the identification and optimisation of a novel pyrimidine-based series of potent and selective SYK inhibitors, where the original aminomethylene group was replaced by a 3,4-diaminotetrahydropyran group...Further modifications of the 3,4-diaminotetrahydropyran group were identified and the interactions of those groups with Asp512 were characterised by protein X-ray crystallography. Further optimisation of this series saw mixed results where permeability and kinase selectivity were increased and oral bioavailability was achieved in the series, but at the expense of potent hERG inhibition.
  • ||||||||||  telaglenastat (CB-839) / Calithera
    Journal:  Allosteric kidney-type glutaminase (GLS) inhibitors with a mercaptoethyl linker. (Pubmed Central) -  Jun 22, 2021   
    Interestingly, the corresponding derivative with an n-propyl (CHCHCH) linker showed substantially lower inhibitory potency (IC = 2.3 μM) while the derivative with a dimethylsulfide (CHSCH) linker showed no inhibitory activity at concentrations up to 100 μM, underscoring the critical role played by the mercaptoethyl linker in the high affinity binding to the allosteric site of GLS. Additional mercaptoethyl-linked compounds were synthesized and tested as GLS inhibitors to further explore SAR within this scaffold including derivatives possessing a pyridazine as a replacement for one of the two thiadiazole moiety.