GDC0152 / Roche - LARVOL DELTA

[Retracted] GDC‑0152 attenuates the malignant progression of osteosarcoma promoted by ANGPTL2 via PI3K/AKT but not p38MAPK signaling pathway. (PubMed, Int J Oncol) - "The Editor apologizes to the readership for any inconvenience caused. [International Journal of Oncology 46: 1651‑1658, 2015; DOI: 10.3892/ijo.2015.2872]."

Journal • Oncology • Osteosarcoma • Sarcoma • Solid Tumor

Tailoring glioblastoma treatment based on longitudinal analysis of post-surgical tumor microenvironment. (PubMed, J Exp Clin Cancer Res) - "Its efficacy was confirmed in vivo by survival analysis and correlated with reversal of the immune profile as well as delayed tumor recurrence.This comprehensive study identified critical time frames and immune cellular targets within the SMe, aiding in the rational design of combination therapies to delay recurrence onset. Our findings suggest that post-surgical systemic injection of GDC-0152 in combination with GemC12-LNC local treatment is a promising and innovative approach for managing GBM recurrence, with potential for future translation to human patient."

Biomarker • Journal • Tumor microenvironment • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor

SMAC mimetic drives microglia phenotype and glioblastoma immune microenvironment. (PubMed, Cell Death Dis) - "To investigate their role in TAMs-related immunosuppression, we antagonized IAP using the central nervous system permeant SMAC mimetic GDC-0152 (SMg)...Altogether, these results demonstrated that SMg drives the immunosuppressive basal microglia toward an active phenotype with pro-apoptotic and anti-tumoral function and modifies the GB immune landscape. This identifies IAP as targets of choice for a potential mechanism-based therapeutic strategy and SMg as a promising molecule for this application."

Journal • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • CASP3 • CD8

Monovalent and Bivalent SMAC Mimetics Reverse HIV Latency and Decreases the HIV Reservoir (CROI 2024) - "Here we investigated whether monovalent and bivalent SMACm could reverse latency and/or deplete the reservoir.Latency reversal by monovalent (GDC0197, GDC0152, LCL161, Xevinapant) and bivalent (AZD5582, BV6) SMACm was assessed in J-Lat 10.6 cells (flow cytometry for GFP expression); the dual-reporter primary CD4+ T cell latency model Morpheus (flow cytometry for productive marker mCherry); and ex vivo CD4+ T cells from PLWH on ART (using HIV transcriptional profiling by digital PCR). Bivalent SMACm can reactivate latent HIV and deplete the reservoir. Monovalent SMACm although less potent in latency reversal, may have a novel role in enhancing clearance of the reservoir through altering antigen presentation and inducing greater CD8+ T cell mediated killing."

Human Immunodeficiency Virus • Infectious Disease • CD4 • CD8

The SMAC mimetic GDC-0152 is a direct ABCB1-ATPase activity modulator and BIRC5 expression suppressor in cancer cells. (PubMed, Toxicol Appl Pharmacol) - "Co-treatment with GDC-0152 restored the sensitivity to the known ABCB1 substrates, including paclitaxel, vincristine, and YM155 in ABCB1-expressing multidrug-resistant cancer cells, and it also restored the sensitivity to tamoxifen in BIRC5-overexpressing tamoxifen-resistant breast cancer cells in vitro...In conclusion, GDC-0152 has the potential for use in the management of cancer patients with ABCB1 and BIRC5-related drug resistance. The findings of our study provide essential information to physicians for designing a more patient-specific GDC-0152 clinical trial program in the future."

Journal • Breast Cancer • Oncology • Solid Tumor • ABCB1 • BIRC5

Integrating bulk and single-cell RNA sequencing data reveals epithelial-mesenchymal transition molecular subtype and signature to predict prognosis, immunotherapy efficacy, and drug candidates in low-grade gliomas. (PubMed, Front Pharmacol) - "In addition, several promising drugs, including birinapant, fluvastatin, clofarabine, dasatinib, tanespimycin, TAK-733, GDC-0152, AZD8330, trametinib and ingenol-mebutate had great potential to the treatment of high risk patients. Our research revealed non-negligible role of EMT in the TME diversity and complexity of LGG. A prognostic signature may contribute to the personalized treatment and prognostic determination."

IO biomarker • Journal • Brain Cancer • CNS Tumor • Glioma • Oncology • Solid Tumor • SLC39A1

Optimized lipopolymers with curcumin to enhance AZD5582 and GDC0152 activity and downregulate inhibitors of apoptosis proteins in glioblastoma multiforme. (PubMed, Biomater Adv) - "Surface FA, Lf and RVG also promoted the ability of the drug-loaded LPs to avoid carcinoma growth. The current FA-, Lf- and RVG-crosslinked LPs carrying AZD, DGC and CURC can be promising in hindering IAP expressions for GBM management."

Journal • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • CASP3 • XIAP

Assessment of monovalent and bivalent SMAC mimetics to both shock and kill the HIV reservoir (IAS-HIV 2023) - " We assessed bivalent (AZD5582, BV6 and Birinapant) and monovalent (GDC0152, GDC0197, xevinapant and LCL161) SMACm in the presence and absence of TNF-a (20ng/ml) in peripheral blood mononuclear cells (PBMC) and sorted CD4+ T-cells from uninfected donors and people with HIV (PWH) on antiretroviral therapy. Bivalent compared to monovalent SMACm induce greater latency reversal and also cell death in cell lines but have similar levels of toxicity in primary cells. The additional of TNF-a did not increase cell death. Further work is continuing on the impact of these compounds on CD4+ T-cells from PWH on ART."

Human Immunodeficiency Virus • Infectious Disease • Oncology • CD4 • TNFA

Perkinsus marinus suppresses in vitro eastern oyster apoptosis via IAP-dependent and caspase-independent pathways involving TNFR, NF-kB, and oxidative pathway crosstalk. (PubMed, Dev Comp Immunol) - "This study challenged hemocytes in vitro with P. marinus for 1 h in the presence or absence of caspase inhibitor Z-VAD-FMK or Inhibitor of Apoptosis protein (IAP) inhibitor GDC-0152...marinus challenge stimulated hemocyte differential expression of oxidation-reduction, TNFR and NF-kB pathways. WGCNA analysis of P. marinus expression in response to hemocyte exposure revealed correlated protease, kinase, and hydrolase expression that could contribute to P. marinus-induced apoptosis suppression."

Journal • Preclinical

Cyclodextrin Reduces Intravenous Toxicity of a Model Compound. (PubMed, J Pharm Sci) - "HP-β-CD alone also increased solubility, but the extent of solubility enhancement was significantly lower than succinic acid alone. Inclusion of HP-β-CD in the solution of GDC-0152 improved blood compatibility, reduced hemolytic potential by ∼20-fold in vitro, and increased the maximum tolerated dose (MTD) to 80 mg/kg."

Journal • Hematological Disorders

Inhibitor of Apoptosis Proteins Determine Glioblastoma Stem-Like Cells Fate in an Oxygen-Dependent Manner. (PubMed, Stem Cells) - "We showed that in a hypoxic environment, IAPs inhibition by GDC-0152, a small-molecule IAPs inhibitor, triggered stem-like cell apoptosis and decreased proliferation in four human glioblastoma cell lines...Our findings provide new insights into the dual mechanism of action of IAPs inhibitors that depends on oxygen level and are relevant to their therapeutic application in tumors. Stem Cells 2019."

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WX20120108, a novel IAP antagonist, induces tumor cell autophagy via activating ROS-FOXO pathway. (PubMed, Acta Pharmacol Sin) - "WX20120108 is an analogue of GDC-0152 (a known IAP antagonist) and displays more potent anti-tumor and autophagy-regulating activity in tumor cells, we investigated the regulatory mechanisms underlying WX20120108-induced autophagy...In conclusion, WX20120108-induced autophagy relies on activating ROS-Foxo3 pathway, which is independent of IAPs. This finding provides a new insight into the mechanism of IAP antagonist-mediated regulation of autophagy."

Journal • Oncology

Smac mimetics LCL161 and GDC-0152 inhibit osteosarcoma growth and metastasis in mice. (PubMed, BMC Cancer) - "These data imply that Smac mimetics can cooperate with TNFα secreted by tumor-associated immune cells to kill osteosarcoma cells in vivo. Smac mimetics may therefore benefit osteosarcoma patients whose tumors contain Smac mimetic-responsive cancer cells and TNFα-producing infiltrating cells."

Journal • Preclinical

Role of Reactive Oxygen Species in GDC-0152-Induced Apoptosis and Autophagy of NB4 cells (PubMed, Zhongguo Shi Yan Xue Ye Xue Za Zhi) - "GDC-0152 inhibits cell proliferation by inducing apoptosis and autophagy of NB4 cells. ROS can promote GDC-0152-induced apoptosis and autophagy of NB4 cells."

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Mutagenic assessment of chemotherapy and Smac mimetic drugs in cells with defective DNA damage response pathways. (PubMed, Sci Rep) - "Doxorubicin and cisplatin provoked mutations in more surviving cells deficient in ATM, p53 or the homologous recombination effector RAD51 than in wild type cells, but suppressing non-homologous end joining (NHEJ) by disabling DNA-PKcs prevented chemotherapy-induced mutagenesis. Vincristine-induced mutagenesis required p53 and DNA-PKcs but was not affected by ATM status, consistent with it provoking ATM-independent p53-mediated activation of caspases and CAD, which creates DNA lesions in surviving cells that could be mis-repaired by NHEJ. Encouragingly, GDC-0152 failed to stimulate mutations in cells with proficient or defective DNA damage response pathways. This study highlights the elevated oncogenic risk associated with treating DNA repair-deficient patients with genotoxic anti-cancer therapies, and suggests a potential advantage for Smac mimetic drugs over traditional therapies: a reduced risk of therapy-related cancers."

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SMAC Mimetics Induce Autophagy-Dependent Apoptosis of HIV-1-Infected Resting Memory CD4+ T Cells. (PubMed, Cell Host Microbe) - "We found that DIABLO/SMAC mimetics (birinapant, GDC-0152, and embelin) selectively kill HIV-T without increasing virus production or targeting uninfected T. Genetic or pharmacological inhibition of autophagy induction, but not autophagy-mediated degradation, abrogated this interaction and subsequent cell death. Our findings identify a mechanism whereby DIABLO/SMAC mimetics exploit autophagy and apoptotic machinery to selectively induce killing of HIV-T without viral reactivation while sparing uninfected cells."

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