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DRUG:

voxtalisib (SAR245409)

i
Associations
Company:
Exelixis, Sanofi
Drug class:
mTOR inhibitor, PI3K inhibitor
Related drugs:
Associations
3ms
p27 Cell Cycle Inhibitor and Survival in Luminal-Type Breast Cancer: Gene Ontology, Machine Learning, and Drug Screening Analysis. (PubMed, J Breast Cancer)
The integration of ML and bioinformatic analyses of p27 has the potential to enhance risk stratification and facilitate personalized treatment strategies for patients with breast cancer.
Journal • Machine learning
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ER (Estrogen receptor) • PGR (Progesterone receptor) • CD8 (cluster of differentiation 8) • CDKN2B (Cyclin Dependent Kinase Inhibitor 2B) • CDKN1A (Cyclin-dependent kinase inhibitor 1A) • CDKN1B (Cyclin dependent kinase inhibitor 1B)
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CDKN1B expression
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serdemetan (JNJ-26854165) • voxtalisib (SAR245409)
over1year
Inverse Impact of Cancer Drugs on Circular and Linear RNAs in Breast Cancer Cell Lines. (PubMed, Noncoding RNA)
However, they display opposite effects, circ/linVRK1 favors apoptosis whereas circ/linMAN1A2 stimulates cell migration, and only XL765 did not alter the ratio of other dangerous circ/linRNAs in MCF-7. In MDA-MB-231 cells, AMG511 and GSK1070916 decreased circGFRA1, as a good response to drugs. Furthermore, some circRNAs might be associated with specific mutated pathways, such as the PI3K/AKT in MCF-7 cells with circ/linHIPK3 correlating to cancer progression and drug-resistance, or NHEJ DNA repair pathway in TP-53 mutated MDA-MB-231 cells.
Preclinical • Journal
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NMI-900 • voxtalisib (SAR245409)
almost2years
Osteosarcoma patient-derived xenografts derived from naive and pretreated metastatic patients with high-risk CDK4/6 hyperactivation signatures are sensitive to dual inhibition of CDK4/6 and PI3K/mTOR (AACR 2023)
These data provide evidence that combination palbociclib+voxtalisib therapy is safe, efficacious, and increases CDK4/6i efficiency in both pretreated and naive PDX models of OS. These studies provide rationale for earlier therapeutic intervention in pediatric and AYA OS patients with CDK4/6 hyperactivation signatures.
Clinical • Metastases
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PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • CDK4 (Cyclin-dependent kinase 4) • CCND3 (Cyclin D3) • CDK1 (Cyclin-dependent kinase 1)
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Ibrance (palbociclib) • voxtalisib (SAR245409)
over2years
TARGETING PI3K/MTOR MITIGATES RESISTANCE TO CDK4/6 INHIBITION IN RB-PROFICIENT PEDIATRIC AND AYA OSTEOSARCOMAS (CTOS 2022)
Once tumor volumes reached ~100mm3, mice were randomized and based on dose-finding studies treated with 5-day cycles of daily treatment with the CDK4/6 inhibitor palbociclib (50 mg/kg) +/- the dual PI3K/mTOR inhibitor voxtalisib (50 mg/kg) for 6-8 weeks. This study is of great significance for it provides strong rationale for earlier therapeutic intervention with a combination therapy targeting CDK4/6 and PI3K/mTOR pathways in a subset of OS patients with CDK4/6 hyperactivation. This therapeutic strategy has the potential to minimize disease burden and enhance quality of life in both the un-pretreated and the pre-treated clinical setting.
Clinical
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RB1 (RB Transcriptional Corepressor 1) • AXL (AXL Receptor Tyrosine Kinase) • CCND3 (Cyclin D3) • CDK1 (Cyclin-dependent kinase 1) • PIK3C3 (Phosphatidylinositol 3-Kinase Catalytic Subunit Type 3)
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Ibrance (palbociclib) • voxtalisib (SAR245409)
over2years
UPLC-MS/MS Technology for the Quantitative Methodology and Pharmacokinetic Analysis of Voxtalisib in Rat Plasma. (PubMed, Front Pharmacol)
Voxtalisib, is a specific, effective, and reversible dual inhibitor, which inhibits both pan-class I phosphoinositide 3-kinase (PI3K) and mechanistic target of rapamycin (mTOR). Finally, the pharmacokinetic profile of the analyte had been availably studied by the UPLC-MS/MS bio-analytical method after rats were treated by intragastric administration with voxtalisib (5 mg/kg). The results indicated that the UPLC-MS/MS technology can effectively and quickly quantify the analyte, and this method can also be used for the pharmacokinetic study of voxtalisib, which can provide reference for the optimization of clinical drug management in the later period.
PK/PD data • Preclinical • Journal
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mTOR (Mechanistic target of rapamycin kinase)
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sirolimus • voxtalisib (SAR245409)
almost3years
Targeting CDK4/6 inhibitor resistance in relapsed RB-proficient osteosarcoma patient-derived xenografts via PI3 Kinase/mTOR inhibition (AACR 2022)
Combination index and Bliss independence analyses indicated that inhibition of OS growth by exposure to CDK4/6i (Palbociclib or Abemaciclib) and PI3K/mTOR inhibitor (PI3K/mTORi-Voxtalisib or LY3023414) was additive-to-synergistic and lead to increased apoptosis at clinically relevant concentrations. Notably, Palbociclib + Voxtalisib was more efficacious than single-agent (p<0.05, Two-way ANOVA; Holm-Sidak). These data highlight the need to optimize CDK4/6i+PI3K/mTORi dosing schedules and provide evidence that Palbociclib + Voxtalisib therapy is safe, efficacious, and can decrease CDK4/6i resistance in aggressive PDX models of OS.
Clinical
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RB1 (RB Transcriptional Corepressor 1) • AXL (AXL Receptor Tyrosine Kinase) • CCND3 (Cyclin D3) • CDK1 (Cyclin-dependent kinase 1) • PIK3C3 (Phosphatidylinositol 3-Kinase Catalytic Subunit Type 3)
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Ibrance (palbociclib) • Verzenio (abemaciclib) • samotolisib (LY3023414) • voxtalisib (SAR245409)
almost3years
UC.183, UC.110, and UC.84 Ultra-Conserved RNAs Are Mutually Exclusive with miR-221 and Are Engaged in the Cell Cycle Circuitry in Breast Cancer Cell Lines. (PubMed, Genes (Basel))
Our results demonstrate that the expression of uc.183, uc.110, and uc.84 T-UCRs is mutually exclusive with miR-221 and is engaged in the regulation of CDKN1B expression. In addition, tests with a set of anticancer drugs, including BYL719, AZD5363, AZD8055, AZD7762, and XL765, revealed the modulation of specific T-UCRs without alteration of miR-221 levels.
Preclinical • Journal
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MIR221 (MicroRNA 221) • CDKN1B (Cyclin dependent kinase inhibitor 1B)
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CDKN1B expression
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Piqray (alpelisib) • Truqap (capivasertib) • AZD8055 • voxtalisib (SAR245409)
3years
Identification of a DNA Methylation-Driven Genes-Based Prognostic Model and Drug Targets in Breast Cancer: In silico Screening of Therapeutic Compounds and in vitro Characterization. (PubMed, Front Immunol)
Furthermore, a in silico screening of druggable targets and compounds from CTRP and PRISM databases was performed, resulting in the identification of five target genes (HMMR, CCNB1, CDC25C, AURKA, and CENPE) and five agents (oligomycin A, panobinostat, (+)-JQ1, voxtalisib, and arcyriaflavin A), which might have therapeutic potential in treating high-risk breast cancer patients. Further in vitro evaluation confirmed that (+)-JQ1 had the best cancer cell selectivity and exerted its anti-breast cancer activity through CENPE. In conclusion, our study provided new insights into personalized prognostication and may inspire the integration of risk stratification and precision therapy.
Preclinical • Journal • Epigenetic controller
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AURKA (Aurora kinase A) • CDC25C (Cell Division Cycle 25C) • CCNB1 (Cyclin B1) • GNRP (Ras-Specific Guanine Nucleotide-Releasing Factor 1)
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JQ-1 • Farydak (panobinostat) • voxtalisib (SAR245409)
4years
Birinapant Enhances Gemcitabine's Anti-tumor Efficacy in Triple-Negative Breast Cancer by Inducing Intrinsic Pathway-Dependent Apoptosis. (PubMed, Mol Cancer Ther)
We next assessed whether birinapant has a synergistic effect with commonly used anti-cancer drugs, including entinostat (class I histone deacetylase inhibitor), cisplatin, paclitaxel, voxtalisib (PI3K inhibitor), dasatinib (Src inhibitor), erlotinib (epidermal growth factor receptor inhibitor), and gemcitabine, in TNBC. Birinapant significantly enhanced the anti-tumor activity of gemcitabine in TNBC both in vitro and in xenograft mouse models through activation of the intrinsic apoptosis pathway via degradation of cIAP2 and XIAP, leading to apoptotic cell death. Our findings demonstrate the therapeutic potential of birinapant to enhance the anti-tumor efficacy of gemcitabine in TNBC by targeting the IAP family of proteins.
Clinical • Journal
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EGFR (Epidermal growth factor receptor) • BIRC3 (Baculoviral IAP repeat containing 3)
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cisplatin • erlotinib • dasatinib • gemcitabine • paclitaxel • Jingzhuda (entinostat) • birinapant (IGM-9427) • voxtalisib (SAR245409)
over4years
[VIRTUAL] Birinapant enhances gemcitabine’s anti-tumor efficacy in triple-negative breast cancer by inducing intrinsic pathway-dependent apoptosis (AACR-II 2020)
Here, we assessed whether birinapant synergizes with commonly used anti-cancer drugs, including entinostat (class I histone deacetylase inhibitor), cisplatin, paclitaxel, voxtalisib (PI3K inhibitor), dasatinib (Src inhibitor), everolimus (mTOR inhibitor), and gemcitabine, in triple-negative breast cancer (TNBC). Our findings demonstrate the therapeutic potential of birinapant for enhancing the anti-tumor efficacy of gemcitabine in TNBC by targeting the IAP family of proteins.
Clinical
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BIRC3 (Baculoviral IAP repeat containing 3)
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cisplatin • dasatinib • gemcitabine • paclitaxel • everolimus • Jingzhuda (entinostat) • birinapant (IGM-9427) • voxtalisib (SAR245409)