- |||||||||| MIV-711 / Medivir
Journal: Synthesis and Biological Evaluation of Novel Piperidine-3-Carboxamide Derivatives as Anti-Osteoporosis Agents Targeting Cathepsin K. (Pubmed Central) - Sep 14, 2024
Molecular docking studies revealed that H-9 formed several hydrogen bonds and hydrophobic interactions with key active-site residues of cathepsin K. In vitro, H-9 demonstrated anti-bone resorption effects that were comparable to those of MIV-711, a cathepsin K inhibitor currently in phase 2a clinical trials for the treatment of bone metabolic disease...Moreover, in vivo experiments showed that H-9 increased the bone mineral density of OVX-induced osteoporosis mice. These results suggest that H-9 is a potent anti-bone resorption agent targeting cathepsin K and warrants further investigation for its potential anti-osteoporosis values.
- |||||||||| birinapant (IGM-9427) / IGM Biosciences, CINelim (terameprocol) / Erimos Pharma, xevinapant (Debio 1143) / EMD Serono
Journal, PARP Biomarker, IO biomarker: Molecular Insights into the Anticancer Activity of Withaferin-A: The Inhibition of Survivin Signaling. (Pubmed Central) - Sep 14, 2024
Furthermore, Wi-AREAL treatment activated apoptosis signaling, as evidenced by reduced PARP-1 and Bcl-2 levels, increased procaspase-3, and elevated Cytochrome C. Additionally, treating cells with a nontoxic low concentration (0.01%) of Wi-AREAL inhibited migration and invasion, as well as EMT (epithelial-mesenchymal transition) signaling. By combining computational and experimental approaches, we demonstrate the potential of Wi-A and Wi-AREAL as natural inhibitors of Survivin, which may be helpful in cancer treatment.
- |||||||||| Olysio (simeprevir) / J&J, Medivir
Journal: PREINCUBATION-DEPENDENT INHIBITION OF ORGANIC ANION TRANSPORTING POLYPEPTIDE 2B1. (Pubmed Central) - Jul 28, 2024
In conclusion, preincubation resulted in inhibitor- and substrate-dependent inhibition of OATP2B1. These results support the conclusion that to reduce the risk of false negative DDI prediction, preincubation should be considered also in OATP2B1 inhibition assays.
- |||||||||| remetinostat (SHP-141) / Medivir
Journal, Epigenetic controller: Soft drug inhibitors for the epigenetic targets lysine-specific demethylase 1 and histone deacetylases. (Pubmed Central) - Jul 15, 2024
We have developed new methyl ester-containing inhibitors targeting LSD1 or HDACs and compared the biological activities of these to their respective carboxylic acid cleavage products. In vitro activity assays, cellular experiments, and a stability assay identified potent HDAC and LSD1 soft drug candidates that are superior to their corresponding carboxylic acids in cellular models.
- |||||||||| TNG348 / Tango Therap
Enrollment change, Trial completion date, Trial termination, Trial primary completion date, Combination therapy: Study to Evaluate TNG348 Alone and With a PARP Inhibitor in Patients With BRCA 1/2 Mutant or HRD+ Solid Tumors (clinicaltrials.gov) - May 31, 2024
P1/2, N=7, Terminated,
Ideally, the cause for the relatively low osimertinib exposure in our evaluation cohort should be known. N=140 --> 7 | Trial completion date: Jun 2026 --> May 2024 | Recruiting --> Terminated | Trial primary completion date: Dec 2025 --> May 2024; Terminated due to safety
- |||||||||| Journal, Combination therapy: Research Progress in the Use of Small Molecule Smac Mimetics in Combination Therapy of Cancer. (Pubmed Central) - May 20, 2024
According to the phase II clinical data, xevinapant has the potential to significantly enhance the standard therapy for patients with head and neck cancer, which is expected to be approved as an innovative therapy for cancer patients. Therefore, this paper briefly describes the mechanism of IAPs (AT-406, APG-1387, GDC- 0152, TL32711, and LCL161) as single or in combination for cancer treatment, their application status as well as the synthetic pathway, and explores the research prospects and challenges of IAPs antagonists in the tumor combination therapy, with the hope of providing strong insights into the further development of Smac mimics in tumor therapy.
- |||||||||| Journal: HCV antiviral drugs have the potential to adversely perturb the maternal-fetal communication axis through inhibition of CYP3A7 DHEA-S oxidation. (Pubmed Central) - May 16, 2024
Therefore, this paper briefly describes the mechanism of IAPs (AT-406, APG-1387, GDC- 0152, TL32711, and LCL161) as single or in combination for cancer treatment, their application status as well as the synthetic pathway, and explores the research prospects and challenges of IAPs antagonists in the tumor combination therapy, with the hope of providing strong insights into the further development of Smac mimics in tumor therapy. Furthermore, paritaprevir, asunaprevir, simeprevir, danoprevir, and glecaprevir all had observed half-maximal inhibitory concentrations between the range of 10 and 20
- |||||||||| Adasuve (staccato loxapine) / AOP Orphan Pharma, Teva, Ferrer International, Galen, Medivir, Tagrisso (osimertinib) / AstraZeneca
Journal: A Validated Assay to Quantify Osimertinib and Its Metabolites, AZ5104 and AZ7550, from Microsampled Dried Blood Spots and Plasma. (Pubmed Central) - May 9, 2024
Furthermore, paritaprevir, asunaprevir, simeprevir, danoprevir, and glecaprevir all had observed half-maximal inhibitory concentrations between the range of 10 and 20 The measurement of osimertinib, AZ5104, and AZ7550 from hemaPEN microsampled DBS is a convenient and reliable approach for therapeutic drug monitoring that produces measurements consistent with plasma drug levels.
- |||||||||| birinapant (IGM-9427) / IGM Biosciences
Journal, IO biomarker: Birinapant Reshapes the Tumor Immunopeptidome and Enhances Antigen Presentation. (Pubmed Central) - Apr 17, 2024
These data suggest that Birinapant can reshape the tumor immunopeptidome with respect to quality and quantity, which improves the presentation of CTA peptides and neoantigens, thus enhancing the immunogenicity of tumor cells. Such changes may be vital to the effectiveness of combination therapy, which can be further transferred to the clinic or aid in the development of new immunotherapeutic strategies to improve the anti-tumor immune response.
- |||||||||| Olysio (simeprevir) / J&J, Medivir, Daklinza (daclatasvir) / BMS
PK/PD data, Journal: Synchronous spectrofluorimetry and chemometric modeling: A synergistic approach for analyzing simeprevir and daclatasvir, with application to pharmacokinetics evaluation. (Pubmed Central) - Apr 6, 2024
Moreover, the proposed models have been applied to determine the pharmacokinetics of simeprevir and daclatasvir, providing valuable insights into their distribution and elimination patterns. Overall, the study demonstrates the effectiveness of synchronous spectrofluorimetry coupled with multivariate calibration optimized by firefly algorithms in accurately determining and quantifying simeprevir and daclatasvir in HCV antiviral treatment, offering potential applications in pharmaceutical formulation analysis and pharmacokinetic studies for these drugs.
- |||||||||| TNG348 / Tango Therap
TNG348 is synergistic with PARP inhibitors in tumor models with elevated replication stress (Section 22) - Mar 5, 2024 - Abstract #AACR2024AACR_6864;
We previously showed that the anti-tumor activity of USP1 inhibition results from disruption of the translesion synthesis DNA damage tolerance pathway, a mechanism of action that is functionally distinct from base excision repair targeted by PARPi...For example, overexpression of oncogenes known to induce replication stress sensitized to the TNG348 and PARPi combination both in vitro and in vivo. These data indicate that cancer-specific elevated DNA replication stress could contribute to tumor sensitivity to TNG348 and provide additional patient stratification strategies and opportunities for indication expansion.
- |||||||||| birinapant (IGM-9427) / IGM Biosciences
Evaluating TNF-receptor associated factor 2 (TRAF2) as a targetable driver of immune resistance in LKB1 deficient non-small cell lung cancer (Section 42) - Mar 5, 2024 - Abstract #AACR2024AACR_6563;
This showed that inhibition of cIAP1 using birinapant was synergistic to CD8 cytotoxicity, as previously known, but the synergy was much more pronounced in STK11 mutant vs STK11-WT context (Bliss index 38, P<1e-10). Together, these data demonstrate that the link between STK11-loss and cIAP1 dysregulation is likely through over-expression of TRAF2, and support the strategy of targeting TRAF2/cIAP1 to overcome immune resistance STK11-deficient NSCLC.
- |||||||||| Identifying novel therapies from unbiased screens in AML with MECOM re-arrangement (Section 29) - Mar 5, 2024 - Abstract #AACR2024AACR_5399;
Co-targeting the other identified druggable vulnerabilities from the drug screen with BETi (mTOR/PI3K with BGT-226 and dactolisib, Bcl-xL with navitoclax and A1155463, as well as CBP/p300 (with GNE781, identified through the CRISPR screen), exerted synergistic lethality in 3q26.2-r AML cells...These findings demonstrate promising preclinical activity of BETi and IAP protein or mTOR/PI3K antagonists in the cellular models of AML with EVI1 overexpression. This supports the rationale to determine in vivo efficacy of these BETi-based combinations against this therapy-resistant AML sub-type.
- |||||||||| birinapant (IGM-9427) / IGM Biosciences
Tumor-extrinsic BIRC3 promote sensitivity to checkpoint inhibition immunotherapy in breast cancer (Section 47) - Mar 5, 2024 - Abstract #AACR2024AACR_5104;
Birinapant, a selective BIRC3 inhibitor, was then used to investigate the effect of BIRC3 blockade on tumor immune microenvironment (TIME) landscape of breast cancer syngeneic mouse models by flow cytometry...Our study revealed a positively association between BIRC3 and anti-tumor immune landscape in breast cancer. Notably, we established a validated prognosis model based on BIRC3 and BIRC3 associated immunomodulators in breast cancer.
- |||||||||| Adasuve (staccato loxapine) / AOP Orphan Pharma, Teva, Ferrer International, Galen, Medivir, Tagrisso (osimertinib) / AstraZeneca
Efficacy and Adverse Events of Osimertinib Correlate With Blood Concentration of Osimertinib and Its Active Metabolites, AZ5104 and AZ7550 (San Diego Convention Center, Room 5A-B (Upper Level)) - Feb 20, 2024 - Abstract #ATS2024ATS_7415;
8 months in the FLAURA study (previously untreated, EGFR mutation-positive advanced NSCLC patients who received either osimertinib or a standard EGFR-tyrosine kinase inhibitor [TKI], such as gefitinib or erlotinib), significantly longer than that of first-generation EGFR-TKIs...[Conclusion] Blood osimertinib concentration may influence PFS. In addition, the active metabolite AZ7550 may correlate with adverse effects, particularly hematologic toxicity.
- |||||||||| birinapant (IGM-9427) / IGM Biosciences
Enrollment change, Trial completion date, Trial termination, 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) - Feb 15, 2024
P1, N=13, Terminated,
In addition, the active metabolite AZ7550 may correlate with adverse effects, particularly hematologic toxicity. N=34 --> 13 | Trial completion date: Jul 2024 --> Dec 2023 | Active, not recruiting --> Terminated | Trial primary completion date: Jul 2024 --> Nov 2023; Drug supply issues
- |||||||||| Adasuve (staccato loxapine) / AOP Orphan Pharma, Teva, Ferrer International, Galen, Medivir
Journal: Alternative Approaches for Addressing Acute Agitation in Schizophrenia and Bipolar Disorder. (Pubmed Central) - Feb 5, 2024
However, US Food and Drug Administration-approved treatments with alternative routes of delivery now include inhaled loxapine powder and, more recently, dexmedetomidine sublingual film...Prim Care Companion CNS Disord 2024;26(1):23nr03596. Author affiliations are listed at the end of this article.
- |||||||||| LCL161 / Novartis, birinapant (IGM-9427) / IGM Biosciences, JP1201 / Joyant Pharma
Journal: SMAC Mimetics for the Treatment of Lung Carcinoma: Present Development and Future Prospects. (Pubmed Central) - Jan 26, 2024
Blood concentrations of trametinib and binimetinib were different in the two groups, highlighting the age-related inter-individual variability of these molecules and the need for TDM. SMAC mimetics acts in a restorative way in the prevention of lung cancer.
- |||||||||| birinapant (IGM-9427) / IGM Biosciences
Enrollment closed, Tumor mutational burden: Birinapant and Intensity Modulated Re-Irradiation Therapy in Treating Patients With Locally Recurrent Head and Neck Squamous Cell Carcinoma (clinicaltrials.gov) - Jan 11, 2024
P1, N=34, Active, not recruiting,
This review highlights the pathogenesis of the virus, disease manifestations, drugs, and vaccines that are being used and those under pipeline for the treatment and prevention of Mpox. Recruiting --> Active, not recruiting
- |||||||||| birinapant (IGM-9427) / IGM Biosciences
Journal: The SMAC mimetic birinapant alleviates lipopolysaccharide-induced acute lung injury by inhibiting MAPK signaling. (Pubmed Central) - Dec 17, 2023
At last, birinapant suppressed the activation of mitogen-activated protein kinase (MAPK) signaling pathway and K48-linked ubiquitinated degradation of TRAF3 in MH-S cells after LPS administration. In conclusion, the results proved that birinapant protected against LPS-induced ALI through inhibiting MAPK activation and K48-linked ubiquitination of TRAF3 in alveolar macrophages.
- |||||||||| Olysio (simeprevir) / J&J, Medivir
Journal: Cryo-EM structures of human organic anion transporting polypeptide OATP1B1. (Pubmed Central) - Dec 17, 2023
These structures reveal major and minor substrate binding pockets and conformational changes during transport. In combination with mutagenesis studies and molecular dynamics simulations, our work comprehensively elucidates the transport mechanism of OATP1B1 and provides the structural basis for DDI predictions involving OATP1B1, which will greatly promote our understanding of OATPs.
- |||||||||| TNG348 / Tango Therap
Enrollment open, Combination therapy: Study to Evaluate TNG348 Alone and With a PARP Inhibitor in Patients With BRCA 1/2 Mutant or HRD+ Solid Tumors (clinicaltrials.gov) - Dec 14, 2023
P1/2, N=140, Recruiting,
In combination with mutagenesis studies and molecular dynamics simulations, our work comprehensively elucidates the transport mechanism of OATP1B1 and provides the structural basis for DDI predictions involving OATP1B1, which will greatly promote our understanding of OATPs. Not yet recruiting --> Recruiting
- |||||||||| Olysio (simeprevir) / J&J, Medivir
Journal, Gene therapy: A simeprevir-inducible molecular switch for the control of cell and gene therapies. (Pubmed Central) - Nov 28, 2023
Here we describe a CID module based on the orally available, approved, small molecule simeprevir and its target, the NS3/4A protease from hepatitis C virus. We demonstrate the utility of this CID module as a molecular switch to control biological processes such as gene expression and apoptosis in vitro, and show that the CID system can be used to rapidly induce apoptosis in tumor cells in a xenograft mouse model, leading to complete tumor regression.
- |||||||||| Phenotypic Drug Response Profiling Identifies Asparaginase-Based Synergistic Combinations for Very High Risk Acute Lymphoblastic Leukaemia (Grand Hyatt - Grand Hall B) - Nov 3, 2023 - Abstract #ASH2023ASH_3029;
We validated combinations of ASNase with the 8 selected drugs plus 4 drugs used in induction therapy (prednisolone, dexamethasone, vincristine and daunorubicin) using a 4x4 drug matrix in 15 high-risk ALL PDX samples...Our results identify XPO1 inhibitors as a new class of drugs with promising anti-leukaemic activity in BCP-ALL. Co-culture based DRP shows promise in identifying alternative novel sensitive synergistic combinations ex-vivo with decreased toxicity for patients who have an inadequate response to standard therapy.
- |||||||||| Actionable Findings from an Unbiased Drug Screen for Novel Single Agent and Combination Therapies Against AML with Mecom Re-Arrangement (SDCC - Halls G-H) - Nov 3, 2023 - Abstract #ASH2023ASH_1826;
This was consistent with previous reports that BET inhibitors (e.g., OTX015, mivebresib or ABBV-075 and JQ1) are effective against 3q26.2-r AML cell lines, patient-derived (PD) AML cells and PDX models...In follow-up experiments, XIAP/cIAPs inhibitors birinapant (10-1000 nM) or SM-164 (30-1000 nM), chosen based on the MIPE screen outcomes, induced significantly more dose-dependent apoptosis in 3q26.2-r versus the other AML cell lines...Treatment with the dual mTOR/PIK3CA inhibitor NVP-BGT226 (1-30 nM) or navitoclax or Bcl-xL-specific BH3 mimetic A-1155463 also exerted lethality and synergistically induced apoptosis with mivebresib in AML cells with inv3/t(3;3)...Co-treatment with birinapant and tegavivint also synergistically induced apoptosis in 3q26.2-r AML cells...Additionally, compared to each drug or vehicle control, co-treatment with birinapant and the BETi OTX015 (30 mg/kg/day, by oral gavage) was more effective in reducing AML burden in the xenograft model. These findings demonstrate promising preclinical activity of IAP protein inhibition against the cellular models of AML with inv3/t(3;3) with EVI1 overexpression, supporting the rationale to further evaluate in vivo efficacy of birinapant and/or BETi-based combinations against this AML sub-type.
- |||||||||| Targeting Mitochondrial Apoptotic Priming State to Personalize Therapy for Relapsed Acute Myeloid Leukemia (SDCC - Ballroom 20CD) - Nov 3, 2023 - Abstract #ASH2023ASH_947;
Overall, we demonstrate that acquired resistance to targeted therapy in AML is accompanied by common mechanism of reduction in mitochondrial priming along with drug-specific resistance mechanisms. Further, we find that, even in the context of a multiply-resistant PDX model, DBP can still identify therapeutic vulnerabilities that can be efficaciously exploited in vivo .
- |||||||||| fostroxacitabine bralpamide (MIV-818) / Medivir
Enrollment closed, Enrollment change, Trial completion date, Trial primary completion date: A Study to Evaluate MIV-818 in Patients With Liver Cancer Manifestations (clinicaltrials.gov) - Sep 11, 2023
P1/2, N=53, Active, not recruiting,
Not yet recruiting --> Recruiting Recruiting --> Active, not recruiting | N=102 --> 53 | Trial completion date: May 2023 --> Feb 2024 | Trial primary completion date: May 2023 --> Feb 2024
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