VS-5584 / Verastem - LARVOL DELTA

PI3K/mTOR Inhibitor VS-5584 Alters Expression of WNT Signaling Genes and Induces Apoptosis in Lung Adenocarcinoma Cells: In Vitro and In Silico Insight. (PubMed, Cell Biochem Biophys) - "The expression of some upregulated DEGs in the datasets decreased in A549 cells treated with VS-5584. VS-5584 shows promise as an anti-cancer agent in the treatment of NSCLC by downregulating the expression of WNT signaling genes."

Journal • Preclinical • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

SIRT2 inhibitor SirReal2 enhances anti-tumor effects of PI3K/mTOR inhibitor VS-5584 on acute myeloid leukemia cells. (PubMed, Cancer Med) - "Taken together, the PI3K/mTOR inhibitor VS-5584 was effective in suppressing AML cell proliferation. PI3K/mTOR inhibitor combined with SIRT2 inhibitor exhibited a synergistic inhibitory effect on AML cells. Our findings offer promising therapeutic strategies and drug candidates for the treatment of AML."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology

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

PI3K/mTOR inhibitor VS-5584 combined with PLK1 inhibitor exhibits synergistic anti-cancer effects on non-small cell lung cancer. (PubMed, Eur J Pharmacol) - "The use of the ROS inhibitor N-acetylcysteine (NAC) effectively reduced ROS levels and decreased the proportion of apoptotic cells. VS-5584 combined with NMS-P937 exhibited a synergistic effect in inhibiting NSCLC cell growth. These findings suggest that VS-5584 has potential as a therapeutic strategy for treating NSCLC."

Journal • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • CASP3 • CDK1 • CDKN1A

The lncRNA expression profile signature of leukemia stem cells is altered upon PI3K/mTOR inhibition: an in vitro and in silico study. (PubMed, Nucleosides Nucleotides Nucleic Acids) - "We suppressed PI3K/Akt/mTOR signaling in LSC and HSC cell-lines by specific PI3K/mTOR dual-inhibitor (VS-5584) and confirmed the inhibition by antibody-array...SRA was predicted to interact with CREB1, RARA, and PPARA. The possible DELs' targets were predicted to form six ontological groups, be highly enriched for phosphoprotein, and be involved in "PPAR signaling pathway" and "ChREBP regulation by carbohydrates and cAMP." These results will help to elucidate the roles of lncRNAs in the mechanisms that provide selective advantages to leukemia stem cells."

Journal • Preclinical • Hematological Malignancies • Leukemia • Oncology • CEBPA • CREB1 • MBD4 • NANOG • PPARA • RELA • SNHG5 • ZEB2

Irisin Attenuates Apoptosis Following Ischemia-Reperfusion Injury Through Improved Mitochondria Dynamics and ROS Suppression Mediated Through the PI3K/Akt/mTOR Axis. (PubMed, Mol Neurobiol) - "Furthermore, the beneficial effects of irisin on NSC-34 cell-survival, mitochondrial function, and ROS generation were reversed by VS-5584, a highly specific PI3K/AKT/mTOR inhibitor...The mechanisms of action of irisin include the attenuation of apoptosis through the prevention of mitochondrial fission and increased mitochondrial fusion and the alleviation of oxidative stress through activation of the PI3K/AKT/mTOR axis. We therefore identify irisin as a much-needed therapeutic for CIRI."

IO biomarker • Journal • Cardiovascular • Reperfusion Injury • BAX • BCL2 • CASP3 • CASP9 • MFN2

SPR965, a PI3K/mTORC1/C2 inhibitor for treatment of chordoma (AACR 2022) - "SPR965 was more active at 1uM than PI3K/mTOR inhibitors VS-5584, Bimiralisib, PF-04691502, WYE-687, Dactolisib, and Voxtalisib in the Kinase Chemogenomic Set. In SF8894 PDX model SPR965 was more efficacious as it produced similar tumor growth inhibition at 12- and 17-fold lower dose than Buparlisib (PI3K) and Palbociclib (CDK4/6) respectively, both these compounds are in phase 2 clinical trials. In CF459 PDX model SPR965 exhibited dose-dependent tumor growth inhibition, and at 10mg/kg profoundly slowed tumor growth compared to Palbociclib. Studies are underway to elucidate potential mechanisms of SPR965 sensitivity."

Late-breaking abstract • Chordoma • Oncology

"Platelets #AAA #activation #aggregation #adhesion #VS5584 https://t.co/9NM3Q0QRlT" (@CrozrX)

"Platelet #AAA activation, Adhesion, aggregation. Interestingly, VS-5584 came up in quite few COVID19 screens. https://t.co/mLM6xkrLkz" (@CrozrX)

Infectious Disease • Novel Coronavirus Disease

PI3K/mTOR dual-inhibition with VS-5584 enhances anti-leukemic efficacy of ponatinib in blasts and Ph-negative LSCs of chronic myeloid leukemia. (PubMed, Eur J Pharmacol) - "Transcriptional regulation resulted in alterations in the expression levels of target mRNAs. Our results highlight PoVS can be a promising treatment strategy for eliminating CML cells and LSCs selectively, with the reduced ponatinib doses."

Clinical • Journal • Chronic Myeloid Leukemia • Hematological Malignancies • Leukemia • Oncology • AKT1S1 • STAT3

"May I predict the future treatment? Vs-6766 (dual RAF MEKi) /Pembrolizumab 💊 or +PI3K mTORC1/2 VS-5584 / +FAKi Defactinib combos? 😎" (@CrozrX)

"Where's vs-5584 (PI3K mTORC1/2)? 🔻🔻https://t.co/mLM6xkrLkz" (@CrozrX)

Antitumor activity and mechanism of resistance of the novel HDAC and PI3K dual inhibitor CUDC-907 in pancreatic cancer. (PubMed, Cancer Chemother Pharmacol) - "Taken together, these findings support the clinical development of CUDC-907 for the treatment of pancreatic cancer and identify compensatory activation of mTOR and MEK/ERK as a possible mechanism of resistance to CUDC-907."

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

"🔺🔺 @__ice9 @farid__jalali platelet ⛔ AAA #activation #aggregation #adhesion vs-5584 PI3K mTORC1/2 #antiviral 🔻🔻 https://t.co/mLM6xkrLkz" (@CrozrX)

Development of a UPLC-MS/MS Method for the Quantification of VS-5584 and Its Application in Pharmacokinetic Studies in Rats. (PubMed, J Anal Methods Chem) - "After administration of 10 mg/kg, VS-5584 was absorbed quickly and reached a peak concentration of 473.2 ± 72.0 ng/mL after 20 min. The established method allows for the quantification of VS-5584 in rat plasma in detail and can be utilized to successfully describe the pharmacokinetic profile of VS-5584."

Journal • PK/PD data • Oncology

VS-5584, a PI3K/mTOR dual inhibitor, exerts antitumor effects on neuroblastomas in vitro and in vivo. (PubMed, J Pediatr Surg) - "VS-5584 blocks the PI3K/mTOR pathway, induces a G0/G1 cell cycle arrest, and exerts antitumor effects on neuroblastomas both in vitro and in vivo."

Journal • Preclinical • Neuroblastoma • Oncology • Retinal Disorders • Solid Tumor

"Another promising potential, vs-5584 PI3K mTORC1/2 combos https://t.co/0ppdR9DuxE" (@CrozrX)

SARS-CoV-2 M inhibitors: identification of anti-SARS-CoV-2 M compounds from FDA approved drugs. (PubMed, J Biomol Struct Dyn) - "Based on comparative molecular simulation and interaction profiling of the screened drugs with SARS-CoV-2 M revealed R428 (-10.5 kcal/mol), Teniposide (-9.8 kcal/mol), VS-5584 (-9.4 kcal/mol), and Setileuton (-8.5 kcal/mol) with stronger stability and affinity than other drugs and N3 inhibitor; and hence, these drugs are advocated for further validation using in vitro enzyme inhibition and in vivo studies against SARS-CoV-2 infection."

FDA event • Journal • Infectious Disease • Novel Coronavirus Disease

BRD4 inhibition sensitizes renal cell carcinoma cells to the PI3K/mTOR dual inhibitor VS-5584. (PubMed, Aging (Albany NY)) - "Furthermore, BRD4 inhibition (by JQ1 and CPI203), knockdown or complete knockout potentiated VS-5584-induced RCC cell death and apoptosis. Collectively, VS-5584 potently inhibits RCC cell proliferation and survival. Its anti-tumor activity is further enhanced by the targeted inhibition of BRD4."

Journal • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor

"Some of the promising therapeutics, such as PI3K mTOR VS-5584, are also potential novel anticoagulant! https://t.co/mLM6xkrLkz" (@CrozrX)

"Article link to the vs-5584 potential novel #anticoagulant https://t.co/fbjHu0JJ1w" (@CrozrX)

"https://t.co/mvLV4qqIIW #Sepsis Platelet AAA #activation #aggregation #adhesion #VTE #DVT #PE #thrombosis VS-5584 PI3K mTOR, novel #anticoagulant potential #COVID19 (thread)" (@CrozrX)

Cardiovascular • Hematological Disorders • Infectious Disease • Novel Coronavirus Disease • Septic Shock • Thrombosis

"Platelet AAA #activation #aggregation #adhesion PI3K mTOR vs-5584 #oncology https://t.co/mLM6xkrLkz" (@CrozrX)

Oncology

CCT128930 induces G1-phase arrest and apoptosis and synergistically enhances the anticancer efficiency of VS5584 in human osteosarcoma cells. (PubMed, Biomed Pharmacother) - "Moreover, CCT128930 treatment obviously enhanced VS5584-induced growth inhibition and apoptosis in human osteosarcoma cells, followed by enhanced PARP cleavage and caspase-3 activation. Taken together, CCT128930 alone or combined treatment with CCT128930 and VS5584 both effectively inhibited human osteosarcoma cells growth by induction of G1-phase arrest and apoptosis through regulating PI3K/mTOR and MAPKs pathways."

Journal • Oncology • Osteosarcoma • Sarcoma • Solid Tumor • CASP3 • CCNB1 • CCND1 • CDK1

"https://t.co/r04pVIMqjl VS-5584 PI3K mTOR #platelet AAA #activation #aggregation #adhesion #PE #VTE #DVT #sepsis #thrombosis" (@CrozrX)

Cardiovascular • Hematological Disorders • Infectious Disease • Septic Shock • Thrombosis