BGT226 / Novartis - LARVOL DELTA

Actionable Findings from an Unbiased Drug Screen for Novel Single Agent and Combination Therapies Against AML with Mecom Re-Arrangement (ASH 2023) - "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...."

Combination therapy • Acute Myelogenous Leukemia • Oncology • BCL2L1 • BRD4 • CASP3 • CDK4 • CTNNB1 • GATA2 • HEXIM1 • MCL1 • MECOM • MYC • PIK3CA • SF3B1 • XIAP

Synergistic Inhibition of PI3K and HSP90 Enhanced Antitumorigenic Efficacy in Adrenocortical Carcinoma. (PubMed, Res Sq) - "Quantitative high-throughput drug combination screening identified potent synergy between phosphatidylinositol-3-kinase (PI3K) inhibitor, PIK75 and heat shock protein 90 (HSP90) inhibitors, Ganetespib (STA9090), HSP990, or Luminespib (NVP-AUY922). Further antitumor efficacy was confirmed by the BGT226-STA9090 combination in human ACC xenograft model and five PDOs with different pathogenic mutations. Conclusively, the combinations of PI3K and HSP90 inhibitors were highly effective in preclinical studies, warranting a clinical trial in patients with advanced ACC."

Journal • Adrenal Cortex Carcinoma • Genito-urinary Cancer • Oncology • Solid Tumor • CDC37 • HSP90AA1

Heterogeneous Activation of Signaling Pathways and Therapeutic Vulnerabilities in KSHV-Associated Primary Effusion Lymphoma Cell Lines. (PubMed, J Med Virol) - "Importantly, dual PI3K/mTOR inhibitors BGT226 and Dactolisib demonstrated superior efficacy by potently inhibiting proliferation and inducing apoptosis and cell cycle arrest in all PEL cell lines, suggesting an advantage in overcoming compensatory feedback mechanisms. These findings underscore the heterogeneity of PEL and the need for personalized therapeutic strategies. Our results support the potential of combinatorial or multi-targeted approaches to improve treatment outcomes for PEL patients and warrant further preclinical and clinical investigations."

Heterogeneity • Journal • Preclinical • Hematological Malignancies • Kaposi Sarcoma • Lymphoma • Oncology • Sarcoma • Solid Tumor

Preclinical Investigation Of Phosphatidylinositol-3-kinase And Heat Shock Protein 90 Inhibitors Combination Therapy In Adrenocortical Carcinoma (ENDO 2025) - "We determined the effective doses and cytotoxicity of the HSP90 inhibitors (STA9090, HSP990, NVP-AUY922) and PI3K inhibitors (PIK-75, BGT-226) and their combinations in preclinical models of ACC. Further validation of synergistic efficacy of BGT226 and STA9090 in NOD SCID-gamma mice showed a reduction in the mean volume of ACC xenografts in STA9090-BGT226 treatment group to 28.4% of the vehicle control group and 38.4% and 37.7 % of those in STA9090-only and BGT226-only groups, respectively. In conclusion, the synergistic combinations of the PI3K and HSP90 inhibitors were effective in preclinical studies of ACC, warranting a clinical trial in patients with advanced ACC."

Combination therapy • Late-breaking abstract • Preclinical • Adrenal Cortex Carcinoma • Genito-urinary Cancer • Oncology • Solid Tumor • AKT2 • CDC37 • HSP90AB1 • PIK3R1

Preclinical Investigation Of Phosphatidylinositol-3-kinase And Heat Shock Protein 90 Inhibitors Combination Therapy In Adrenocortical Carcinoma (ENDO 2025) - "We determined the effective doses and cytotoxicity of the HSP90 inhibitors (STA9090, HSP990, NVP-AUY922) and PI3K inhibitors (PIK-75, BGT-226) and their combinations in preclinical models of ACC. Further validation of synergistic efficacy of BGT226 and STA9090 in NOD SCID-gamma mice showed a reduction in the mean volume of ACC xenografts in STA9090-BGT226 treatment group to 28.4% of the vehicle control group and 38.4% and 37.7 % of those in STA9090-only and BGT226-only groups, respectively. In conclusion, the synergistic combinations of the PI3K and HSP90 inhibitors were effective in preclinical studies of ACC, warranting a clinical trial in patients with advanced ACC."

Combination therapy • Preclinical • Adrenal Cortex Carcinoma • Genito-urinary Cancer • Oncology • Solid Tumor • AKT2 • CDC37 • HSP90AB1 • PIK3R1

Identifying novel therapies from unbiased screens in AML with MECOM re-arrangement (AACR 2024) - "Consistent with this, co-treatment of mivebresib with SMAC mimetic birinapant or IAP inhibitor LCL161 was synergistically lethal against 3q26.2-r cells. 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."

Acute Myelogenous Leukemia • Oncology • BCL2L1 • BRD4 • CASP3 • CDK4 • HEXIM1 • MCL1 • MECOM • mTOR • MYC • PIK3CA • XIAP

PIK Your Poison: The Effects of Combining PI3K and CDK Inhibitors against Metastatic Cutaneous Squamous Cell Carcinoma In Vitro. (PubMed, Cancers (Basel)) - "This study investigates the potential of targeted inhibition of the p110α-subunit of PI3K with PIK-75 or BGT226 (P13Ki), and of CDK1/2/5/9 with dinaciclib (CDKi) as single agents and in combination. The differential responses between the cell lines correlated with driver gene mutation profiles. These findings suggest that personalised medicine approaches targeting PI3K and CDK pathways in combination may yield some benefit for mcSCC, and that more complex 3D models should be considered for drug responsiveness studies in this disease."

Journal • Metastases • Preclinical • Non-melanoma Skin Cancer • Oncology • Skin Cancer • Squamous Cell Carcinoma • Squamous Cell Skin Cancer • CDK1 • PIK3CA

In Silico Identification of Therapeutic Targets and Novel Drug Candidates for Malignant Peripheral Nerve Sheath Tumors. (PubMed, Front Biosci (Landmark Ed)) - "Overall, our results describe the importance of Twist1 in MPNST pathogenesis. Everolimus was also found to be a potential therapeutic drug for MPNSTs."

Journal • Brain Cancer • Fibrosis • Neurofibromatosis • Neurofibrosarcoma • Oncology • Sarcoma • Solid Tumor • TWIST1

CUDC-907, a dual PI3K/histone deacetylase inhibitor, increases meta-iodobenzylguanidine uptake (I-mIBG) in vitro and in vivo: a promising candidate for advancing theranostics in neuroendocrine tumors. (PubMed, J Transl Med) - "Upregulation of the NET by CUDC-907 lead to a better internalization of mIBG in vitro and in vivo."

Epigenetic controller • Journal • Preclinical • CNS Tumor • Endocrine Cancer • Neuroblastoma • Neuroendocrine Tumor • Oncology • Solid Tumor

High-throughput and targeted drug screens identify pharmacological candidates against MiT-translocation renal cell carcinoma. (PubMed, J Exp Clin Cancer Res) - "The results of the high-throughput drug screen and validation studies in TFE3-RCC tumor-derived cell lines have provided in vitro and in vivo preclinical data supporting the efficacy of the PI3K/mTOR inhibitor NVP-BGT226, the transcription inhibitor Mithramycin A, and GPNMB-targeted antibody-drug conjugate CDX-011 as potential therapeutic options for treating advanced MiT-RCC. The findings presented here should provide the basis for designing future clinical trials for patients with MiT-driven RCC."

Journal • Genito-urinary Cancer • Oncology • Ophthalmology • Renal Cell Carcinoma • Solid Tumor • GPNMB • MITF • TFE3 • TFEB

Synergistic efficacy of HSP90 and PI3K inhibitors in adrenocortical carcinoma (AACR 2023) - "Preclinical in vitro studies were performed to validate the efficacy of HSP90 inhibitors (STA9090, AUY922, HSP990), with PI3K inhibitors; PIK75 (investigational) or clinically available BGT226, and their pairwise combinations, in NCI-H295R and SW13 ACC cells. Conclusively, combination of HSP90 and PI3K inhibitors demonstrated a promising in vitro synergistic efficacy by inhibiting the key oncogenic targets of ACC. Further validation of in vivo efficacy is warranted."

Clinical • Adrenal Cortex Carcinoma • Genito-urinary Cancer • Oncology • Solid Tumor • AKT1 • AKT2 • CASP3 • CDH2 • CDK1 • CDK4 • HSP90AA1 • HSP90AB1 • TWIST1 • VIM • ZEB1

ATM-SPARK: A GFP phase separation-based activity reporter of ATM. (PubMed, Sci Adv) - "Furthermore, BGT226 sensitizes cancer cells to the radiomimetic drug neocarzinostatin, suggesting that BGT226 might be combined with radiotherapeutic treatment. ATM-SPARK achieves large dynamic range, bright fluorescence, and simple signal pattern."

Journal • Ataxia • Immunology • Movement Disorders • Oncology • Primary Immunodeficiency

A high-throughput screening platform identifies novel combination treatments for Malignant Peripheral Nerve Sheath Tumors. (PubMed, Mol Cancer Ther) - "The other three combinations, all involving Panobinostat (combined with NVP-BGT226, Torin 2, or Carfilzomib), did not reduce the tumor volume in vivo at non-cytotoxic doses. Our results support the utility of our screening platform of in vitro and in vivo models to explore new therapeutic approaches for MPNSTs and identified that combination MK-1775 with Doxorubicin could be a good pharmacological option for the treatment of these tumors."

Journal • Brain Cancer • Fibrosis • Genetic Disorders • Neurofibromatosis • Neurofibrosarcoma • Oncology • Sarcoma • Soft Tissue Sarcoma • Solid Tumor • NF1 • TP53

Combination PI3K/CDK inhibitors potently effect cutaneous squamous cell carcinoma survival and progression in vitro (LCC 2022) - " Multiple PI3K and CDK inhibitors were found to potently inhibit cell line viability, notably the PI3K inhibitors PIK-75 & BGT226, as well as the CDK inhibitor Dinaciclib. Combination PI3K/CDK inhibitors had a profound impact upon metastatic cSCC. Such treatment may alleviate mechanisms of resistance in vivo, although response may be reliant upon the individual mutational status of the patient."

IO biomarker • Preclinical • Genetic Disorders • Non-melanoma Skin Cancer • Oncology • Skin Cancer • Squamous Cell Carcinoma • Squamous Cell Skin Cancer • PIK3CA • PIK3CG

[VIRTUAL] Activated Phosphoinositide 3-kinase/AKT/mTOR Signaling Reduces Sensitivity to Tumor Treating Fields (TTFields) (ASTRO 2021) - "Finally, we characterized the mechanism of resistance by examining the in vitro efficacy of continued long-term application of TTFields in combination with pharmacological inhibitors including a PI3K/mTOR dual inhibitor (BGT226), and Pan- and isoform-specific inhibitors of PI3K (alpelisib, pictilisib, and BKM120), using cell count, apoptosis, and colony formation assays. Our study demonstrates that the PI3K/ AKT/ mTOR signaling pathway confers resistance to TTFields. This provides a rationale for the combined targeting of PI3K in patients treated with TTFields."

Brain Cancer • Glioblastoma • Glioma • Lung Cancer • Malignant Pleural Mesothelioma • Mesothelioma • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Activated Phosphoinositide 3-Kinase/AKT/mTOR Signaling Confers Resistance to Tumor Treating Fields (TTFields). (PubMed, Int J Radiat Oncol Biol Phys) - "Our study demonstrates that the PI3K/ AKT/ mTOR signaling pathway confers resistance to TTFields. This provides a rationale for the combined targeting of PI3K in patients treated with TTFields."

Journal • Brain Cancer • Glioblastoma • Glioma • Lung Cancer • Malignant Pleural Mesothelioma • Mesothelioma • Non Small Cell Lung Cancer • Oncology • Solid Tumor

[VIRTUAL] Decreased cancer cell sensitivity to Tumor Treating Fields (TTFields) is associated with activation of the PI3K/AKT/mTOR signaling pathway (EANO 2021) - "Our study demonstrates that the PI3K/AKT/mTOR signaling pathway is involved in decreased cellular sensitivity to long-term TTFields application and provide rational for combining PI3K or PI3K/mTOR dual inhibitors with TTFields in clinical trials."

Brain Cancer • Glioblastoma • Lung Cancer • Malignant Pleural Mesothelioma • Mesothelioma • Non Small Cell Lung Cancer • Oncology • Ovarian Cancer • Solid Tumor

[VIRTUAL] Targeting Akt signaling pathway potentiates the antitumor effect of Tumor Treating Fields (TTFields) in vitro (AACR 2021) - "While long-duration application of TTFields led to Akt activation, TTFields in combination with BGT226 resulted in reduction of p-AKT S473, with a corresponding blockade of proliferation, induction of apoptosis, and decrease in the clonogenic potential.Conclusions We propose here a new mechanism of resistance to prolonged TTFields treatment mediated by the PI3K/mTOR/AKT signaling pathway in glioma and ovarian cancer cells. We demonstrate that combination therapy of TTFields and a targeted PI3K/mTOR dual inhibitor (BGT226) inhibited AKT S473 phosphorylation and sensitized cancer cells to “long-duration” TTFields application."

Preclinical • Glioblastoma • Glioma • Lung Cancer • Malignant Pleural Mesothelioma • Mesothelioma • Oncology • Ovarian Cancer • Solid Tumor

CC-223, NSC781406, and BGT226 Exerts a Cytotoxic Effect Against Pancreatic Cancer Cells via mTOR Signaling. (PubMed, Front Pharmacol) - "Finally, we found that Sestrin2 knockdown could inhibit the growth of pancreatic cancer in vivo. In conclusion, these findings suggest that Sestrin2 may promote the occurrence and development of pancreatic cancer through mTOR signaling."

Journal • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Solid Tumor

[VIRTUAL] High-throughput small molecule screens reveal therapeutic opportunities against TFE3-fusion renal cell carcinoma (AACR-NCI-EORTC 2020) - "The SRC inhibitor Dasatinib, the RNA synthesis inhibitor Mithramycin and the PI3K/mTOR inhibitor NVP-BGT226 presented significant antitumor activities in vivo as single agents. PI3K/mTOR pathway inhibitors (NVP-BGT226), transcription inhibitors (Mithramycin), and combinations among each other and with the antibody-drug conjugate CDX-011, show promising preclinical efficacy against TFE3-fusion RCC. This preclinical study provides an unbiased foundation to identify potential therapeutic approaches against TFE3-fusion RCC patients."

Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • BIRC5 • TFE3

Synergistic anti-tumor effects of a novel phosphatidyl inositol-3 kinase/mammalian target of rapamycin dual inhibitor BGT226 and gefitinib in non small cell lung cancer cell lines (Cancer Lett) - “The combination of BGT226 and gefitinib exhibited supra-additive growth inhibitory effects in PC-9 and HCC827 cells. Apoptotic induction and the inhibition of PI3K/mTOR signaling were enhanced by the combination.” 

Preclinical • Non Small Cell Lung Cancer • Oncology

In Vitro and in Vivo Activity of mTOR Kinase and PI3K Inhibitors Against Leishmania donovani and Trypanosoma brucei. (PubMed, Molecules) - "The results of a visceral leishmaniasis mouse model indicated that treatment with Torin2, dactolisib, or NVP-BGT226 resulted in reductions of 35%, 53%, and 54%, respectively, in the numbers of liver parasites. Multiple sequence and structural alignment results indicated high similarities between mTOR and kinetoplastid TORs; the inhibitors are predicted to bind in a similar manner. Taken together, these results indicated that the TOR pathways of parasites have potential for the discovery of novel targets and new potent inhibitors."

Journal • Preclinical

Phase I study of BGT226, a pan-PI3K and mTOR inhibitor, in Japanese patients with advanced solid cancers. (PubMed, Cancer Chemother Pharmacol) - "Treatment with BGT226 did not change any of the biomarkers in neither normal skin nor tumor tissues. BGT226 was tolerated up to 100 mg three times a week in Japanese patients with solid cancers, without difference in toxicity profiles and pharmacokinetics compared to Western patients."

Biomarker • Clinical • Journal • P1 data

Chemoproteomic selectivity profiling of PIKK and PI3K kinase inhibitors. (PubMed, ACS Chem Biol) - "This is achieved by inclusion of two affinity probes derived from the clinical PI3K/MTOR inhibitors Omipalisib and BGT226. The results further show that NVP-BEZ235 is not a PI3K inhibitor. Surprisingly, the designated ATM inhibitor CP466722 was found to bind strongly to ALK2, identifying a new chemotype for drug discovery to treat fibrodysplasia ossificans progressiva."

Journal

Drug Repurposing for Paracoccidioidomycosis Through a Computational Chemogenomics Framework. (PubMed, Front Microbiol) - "...Two antineoplastic drug candidates (vistusertib and BGT-226) predicted to be inhibitors of phosphatidylinositol 3-kinase TOR2 showed antifungal activity at low micromolar concentrations (<10 μM). Four antifungal azole drugs (bifonazole, luliconazole, butoconazole, and sertaconazole) showed antifungal activity at low nanomolar concentrations, validating our methodology. The results suggest our strategy for predicting new anti-PCM drugs is useful. Finally, we could recommend hit-to-lead optimization studies to improve potency and selectivity, as well as pharmaceutical formulations to improve oral bioavailability of the antifungal azoles identified."

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