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  • ||||||||||  Novel Antipsychotics and Risk of Drug-Induced Movement Disorders and Tardive Syndromes (Poster Station: 21) -  Sep 22, 2022 - Abstract #MDSCongress2022MDR_Congress_501;    
    Compared to oral paliperidone, the LAI may decrease risk of DIMDs while LAI risperidone and aripiprazole have equal risk compared to oral formulations. Furthermore, new experimental drug targets that do not use dopamine receptor blockade show promise in reducing incidence of DIMDs.
  • ||||||||||  Ganovo (danoprevir) / Roche, Ascletis, Pfizer, Olysio (simeprevir) / J&J, Medivir
    Journal:  A fuzzy logic-based computational method for the repurposing of drugs against COVID-19. (Pubmed Central) -  Aug 22, 2022   
    It can be concluded that the similarity-based drug repurposing techniques may be the most suitable option for managing emerging diseases such as COVID-19 and can be applied to a wide range of data. Also, fuzzy logic-based scoring methods can produce outcomes which are more consistent with the real-world biological applications than others.
  • ||||||||||  birinapant (IGM-9427) / IGM Biosciences
    Journal:  Interaction of LATS1 with SMAC links the MST2/Hippo pathway with apoptosis in an IAP-dependent manner. (Pubmed Central) -  Aug 11, 2022   
    Finally, we show that LATS1-SMAC interaction is regulated by the SMAC mimetic Birinapant, which requires C-IAP1 inhibition and the degradation of XIAP, suggesting that the MST2 pathway is part of the mechanism of action of Birinapant. Overall, the current work shows that SMAC-dependent apoptosis is regulated by the LATS1 tumour suppressor and supports the idea that LATS1 is a signalling hub that regulates the crosstalk between the MST2 pathway, the apoptotic network and the ERK pathway.
  • ||||||||||  birinapant (IGM-9427) / IGM Biosciences
    Trial completion date, Trial primary completion date, Tumor mutational burden:  Birinapant and Intensity Modulated Re-Irradiation Therapy in Treating Patients With Locally Recurrent Head and Neck Squamous Cell Carcinoma (clinicaltrials.gov) -  Aug 3, 2022   
    P1,  N=34, Recruiting, 
    Overall, the current work shows that SMAC-dependent apoptosis is regulated by the LATS1 tumour suppressor and supports the idea that LATS1 is a signalling hub that regulates the crosstalk between the MST2 pathway, the apoptotic network and the ERK pathway. Trial completion date: Jul 2022 --> Jul 2023 | Trial primary completion date: Jul 2022 --> Jul 2023
  • ||||||||||  Iclusig (ponatinib) / Takeda, Otsuka, Incyte, Olysio (simeprevir) / J&J, Medivir, Tasigna (nilotinib) / Novartis, Inhibikase
    FDA event, Journal:  Repurposing of FDA-approved drugs as autophagy inhibitors in tumor cells. (Pubmed Central) -  Jul 23, 2022   
    We anticipate from our computational results that these drugs may become potent candidates to inhibit autophagy and exhibit the apoptosis in the tumor microenvironment and combat the current limitation of potent autophagy inhibitors; however, to substantiate our in-silico results, further experimental validations of these drug molecules are currently in progress. Communicated by Ramaswamy H. Sarma.
  • ||||||||||  birinapant (IGM-9427) / IGM Biosciences
    Preclinical, Journal:  RB loss determines selective resistance and novel vulnerabilities in ER-positive breast cancer models. (Pubmed Central) -  Jul 9, 2022   
    Using organoid culture and xenograft models, we demonstrate the highly selective use of birinapant based combinations for the treatment of RB-deficient tumors. Together, these data illustrate the critical role of RB-pathway in response to many agents used to treat ER+ breast cancer, whilst informing new therapeutic approaches that could be deployed against resistant disease.
  • ||||||||||  Invirase (saquinavir) / Roche, Olysio (simeprevir) / J&J, Medivir
    Journal:  Repurposing antiviral drugs against HTLV-1 protease by molecular docking and molecular dynamics simulation. (Pubmed Central) -  May 26, 2022   
    The MD simulation confirmed the stability of Simeprevir-protease, Atazanavir-Protease, and Saquinavir-Protease interactions. Clearly, these compounds should be further evaluated in experimental assays and clinical trials to confirm their actual activity against HTLV-1 infection.Communicated by Ramaswamy H. Sarma.
  • ||||||||||  LCL161 / Novartis, birinapant (IGM-9427) / IGM Biosciences, sotrastaurin (AEB071) / Novartis
    HIGH-THROUGHPUT EVALUATION OF THE POTENTIAL OF CANCER DRUGS TO ENHANCE NATURAL KILLER CELL IMMUNOTHERAPY IN CHRONIC MYELOID LEUKEMIA. (Hall Stolz 1-2) -  May 13, 2022 - Abstract #EHA2022EHA_2672;    
    For example, dasatinib and imatinib have been suggested to enhance NK cell cytotoxicity through regulation of activating and inhibitory receptors...The SMAC mimetics birinapant and LCL-161 were the most potent enhancers of NK cell cytotoxicity and had no effect on target cells alone...On the contrary, cytotoxicity-inhibiting drugs included previously known immunosuppressive drugs dexamethasone and prednisolone, as well as novel candidates, such as sotrastaurin, a PKC inhibitor...Conclusion We discovered novel drug classes, which had both activating and inhibitory effects on the NK cell cytotoxicity against CML cells in vitro. Defining NK cell - drug - CML cell interactions in a high-throughput setting provides a framework for future combination immunotherapies to further improve treatment-free remission in CML.
  • ||||||||||  Preclinical, Journal:  In Vitro Assessment of Transporter Mediated Perpetrator DDIs for Several Hepatitis C Virus Direct-Acting Antiviral Drugs and Prediction of DDIs with Statins Using Static Models. (Pubmed Central) -  May 6, 2022   
    Inhibitory effects of asunaprevir, daclatasvir, grazoprevir, paritaprevir, simeprevir, and voxilaprevir, direct-acting antiviral (DAA) drugs for the treatment of chronic hepatitis C virus (HCV) infection, were evaluated in vitro against a range of clinically important drug transporters...Furthermore, we refined and developed static models to predict complex DDIs with several statins (pitavastatin, rosuvastatin, atorvastatin, and pravastatin) by mechanistically assessing differential inhibitory effects of perpetrator drugs on multiple transporters, such as organic anion transporting polypeptides (OATP1B), breast cancer resistance protein (BCRP), multidrug resistance protein 2 (MRP2), organic anion transporter 3 (OAT3), and cytochrome P450 CYP3A enzyme, as they are known to contribute to absorption, distribution, metabolism and excretion (ADME) of above statins...Our studies suggest that mechanistic static model is a promising and useful tool to provide more accurate prediction of the risk and magnitude of DDIs with statins in early drug development and may help to improve the management of clinical DDIs for HCV drugs to ensure effective and safe HCV therapy. GRAPHICAL ABSTRACT.
  • ||||||||||  Tagrisso (osimertinib) / AstraZeneca
    Journal:  The Influence of CYP3A4 Genetic Polymorphism and Proton Pump Inhibitors on Osimertinib Metabolism. (Pubmed Central) -  Apr 2, 2022   
    We found that the AUC, AUC, and C of osimertinib decreased significantly after co-administration with rabeprazole orally, but they increased remarkably when osimertinib was administered through intraperitoneal injection. Taken together, our data demonstrate that the genetic polymorphism and proton pump inhibitors remarkably influence the disposition of osimertinib, thereby providing basic data for the precise application of osimertinib.
  • ||||||||||  birinapant (IGM-9427) / IGM Biosciences
    Journal, Combination therapy:  Efficacy of birinapant in combination with carboplatin in targeting platinum‑resistant epithelial ovarian cancers. (Pubmed Central) -  Mar 23, 2022   
    This combination therapy was also effective in vitro and in vivo in targeting a platinum‑resistant patient‑derived xenograft (PDX) model established from one of the patient tumors tested. Overall, our study demonstrated that birinapant and carboplatin combination could target a subset of platinum‑resistant ovarian cancers and also highlights the potential of the 3D organoid bioassay as a preclinical tool to assess the response to chemotherapy or targeted therapies in ovarian cancer.
  • ||||||||||  adavosertib (AZD1775) / AstraZeneca, birinapant (IGM-9427) / IGM Biosciences
    Combination treatment with cIAP and WEE1 inhibitors exhibits synergism in HPV-positive and HPV-negative head and neck squamous carcinoma cells (Section 5) -  Mar 9, 2022 - Abstract #AACR2022AACR_5536;    
    These results were confirmed by increased levels of apoptosis as demonstrated by flow cytometry and both early and sustained cell growth inhibition over time in impedance assays. Ongoing studies include additional characterization of the downstream effects of these agents on NF-κB pro-survival signaling and the cell cycle, along with evaluation in a preclinical murine xenograft model with combined radiotherapy.
  • ||||||||||  USP1 inhibitor / Tango Therap
    USP1 inhibitor synthetic lethality in BRCA1-mutant cancer is driven by PCNA ubiquitination (Section 22) -  Mar 9, 2022 - Abstract #AACR2022AACR_4668;    
    Our studies suggest that USP1 and PARP1 inhibitors target BRCA1-mutant cancer though distinct yet synergistic mechanisms. As such, USP1 inhibitors may provide novel treatment strategies for PARP1 inhibitor-resistant and -naïve BRCA1-mutant cancer.
  • ||||||||||  birinapant (IGM-9427) / IGM Biosciences, IGM-8444 / IGM Biosciences
    Anti-DR5 agonist IgM antibody IGM-8444 combined with SMAC mimetic birinapant induces strong synergistic tumor cytotoxicity (Section 21) -  Mar 9, 2022 - Abstract #AACR2022AACR_3255;    
    P1
    In summary, combined targeting of the extrinsic and intrinsic apoptotic pathways with IGM-8444 and birinapant respectively enhances tumor cytotoxicity in multiple preclinical models. The combination of IGM-8444 with birinapant is currently under evaluation in a Phase 1 study in patients with relapsed and/or refractory solid cancers (NCT04553692).
  • ||||||||||  birinapant (IGM-9427) / IGM Biosciences
    Integrative approaches to modulate antigen presentation and boost cancer immune response (Section 18) -  Mar 9, 2022 - Abstract #AACR2022AACR_2408;    
    We experimentally validated that the SMAC mimetic birinapant upregulates MHC-I, sensitizes cancer cells to T cell-dependent killing, and adds to ICB efficacy...We found that a higher cancer-cell-intrinsic MHC-II level is significantly associated with better anti-PD-1 response, and that the Hippo signaling pathway can regulate MHC-II expression in melanoma cells. Our findings provide preclinical rationales for increasing cancer cell MHC-I/MHC-II expression to enhance sensitivity to immunotherapy.
  • ||||||||||  Olysio (simeprevir) / J&J, Medivir
    Journal:  Enhanced fitness of hepatitis C virus increases resistance to direct-acting antivirals. (Pubmed Central) -  Mar 8, 2022   
    Beneficial substitutions hyperstimulated phosphatidylinositol 4-phosphate during DAA treatment, and showed decreased dependence on cyclophilins during cyclosporine A treatment, indicating an interplay of virus-host molecular mechanisms in beneficial substitution selection that may necessitate infectious virus production. This comprehensive study demonstrates a possible role for HCV fitness of overcoming drug-mediated selection pressure.
  • ||||||||||  cisplatin / Generic mfg.
    Journal:  Inhibition of cIAP1 in the effective suppression of chemotherapy‑resistant hepatoblastoma. (Pubmed Central) -  Mar 4, 2022   
    Birinapant was substantially more effective against the Huh6‑CDDP cells than against the Huh6 wild‑type cells. Taken together, these findings suggest that repeated exposure to CDDP enhances cIAP1 expression in HB cells and that birinapant is a promising therapeutic drug for CDDP‑resistant HB.
  • ||||||||||  birinapant (IGM-9427) / IGM Biosciences
    Journal, Checkpoint inhibition, PD(L)-1 Biomarker, IO biomarker:  Therapeutically increasing MHC-I expression potentiates immune checkpoint blockade. (Pubmed Central) -  Feb 19, 2022   
    Our findings provide preclinical rationale for treating tumors expressing low MHC-I expression with SMAC mimetics to enhance sensitivity to immunotherapy. The approach used in this study can be generalized to identify other drugs that enhance immunotherapy efficacy.
  • ||||||||||  Journal:  4'-Modified Nucleosides for Antiviral Drug Discovery: Achievements and Perspectives. (Pubmed Central) -  Feb 19, 2022   
    P=N/A, P3
    FNC cured the COVID-19 disease in almost all patients and showed better therapeutic efficacy than remdesivir. In this Account, we provide an overview of 4'-modified nucleoside analogs in clinical stages for antiviral therapies, highlighting the drug discovery strategies, structure-activity relationship studies, and preclinical/clinical studies and also give our perspectives on nucleoside-based antiviral drug discovery.
  • ||||||||||  fostroxacitabine bralpamide (MIV-818) / Medivir
    Enrollment open:  A Study to Evaluate MIV-818 in Patients With Liver Cancer Manifestations (clinicaltrials.gov) -  Feb 11, 2022   
    P1/2,  N=102, Recruiting, 
    In this Account, we provide an overview of 4'-modified nucleoside analogs in clinical stages for antiviral therapies, highlighting the drug discovery strategies, structure-activity relationship studies, and preclinical/clinical studies and also give our perspectives on nucleoside-based antiviral drug discovery. Active, not recruiting --> Recruiting
  • ||||||||||  Adasuve (staccato loxapine) / AOP Orphan Pharma, Teva, Ferrer International, Galen, Medivir
    Clinical, Journal, Adverse events, Serious adverse event:  Rates of adverse and serious adverse events in children with cystic fibrosis. (Pubmed Central) -  Feb 10, 2022   
    AEs occur commonly in pediatric CF clinical trial participants. Season of enrollment could affect AE rates.
  • ||||||||||  Olysio (simeprevir) / J&J, Medivir
    Preclinical, Journal:  Effects of simeprevir on the replication of SARS-CoV-2 in vitro and in transgenic hACE2 mice. (Pubmed Central) -  Jan 21, 2022   
    In a transgenic hACE2 mouse model of SARS-CoV-2 infection, intraperitoneal administration of simeprevir at 10 mg/kg/day for 3 consecutive days failed to suppress viral replication. These findings collectively imply that simeprevir does not inhibit SARS-CoV-2 in vivo and therefore do not support its application as a treatment against COVID-19 at a dosage of 10 mg/kg/day.