BKM120 (NVP-BKM120) is a novel phosphatidylinositol 3-kinase (PI3K) inhibitor and is currently being investigated in phase I clinical trials in solid tumors. Unlike other inhibitors, it does not inhibit the related kinases-mTOR and Vps34. BKM120 (NVP-BKM120) has shown significant cell growth inhibition and induction of apoptosis in a variety of tumor cell lines as well as in animal models, it decreases the cellular levels of p-Akt in mechanistic models and relevant tumor cell lines, as well as downstream effectors in a concentration-dependent and pathway-specific manner. Tested in a panel of 353 cell lines, BKM120 (NVP-BKM120) exhibited preferential inhibition of tumor cells bearing PIK3CA mutations, in contrast to either KRAS or PTEN mutant models. BKM120 treatment significantly inhibits tumor growth in vivo and prolongs the survival of myeloma-bearing mice. In addition, it shows synergistic cytotoxicity with dexamethasone in dexamethasone-sensitive MM cells. BKM120 (NVP-BKM120) behaves synergistically when combined with either targeted agents such as MEK or HER2 inhibitors or with cytotoxic agents such as docetaxel or temozolomide.
Cancer Biol Ther. 2018 May 25;1-20.
Preclinical evaluation of novel PI3K/mTOR dual inhibitor SN202 as potential anti-renal cancer agent
BKM120 (Buparlisib) purchased from AbMole
BioRxiv. 2017 July 18;1-45.
PIK3CAH1047R-induced paradoxical ERK activation results in resistance to BRAFV600E specific inhibitors in BRAFV600E PIK3CAH1047R double mutant thyroid tumors.
BKM120 (Buparlisib) purchased from AbMole
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Source | Cancer Biol Ther (2018). Figure 3. BKM120 (AbMole BioScience) |
| Method | CCK-8 assay | |
| Cell Lines | RCC 786-0 cell line | |
| Concentrations | 10 mmol/L | |
| Incubation Time | 48 or 72 h | |
| Results | These IC50 values were obviously lower than that of the compounds BEZ235 and BKM120, which may be promising candidates for development as new drugs targeting the PI3K pathway. |
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Source | BioRxiv (2017). Figure 6. BKM-120 (Abmole Bioscience, Hong-Kong, China) |
| Method | western blot | |
| Cell Lines | 8505c cells | |
| Concentrations | 1 μM | |
| Incubation Time | ||
| Results | In this case, BKM-120 similarly abrogated the paradoxical effect seen in OCUT-2, demonstrating that the phenomenon observed is unlikely to be caused by a possible off-target effect of GDC-0941 but was rather specific to its inhibitory effect on PI3’K activity. |
| Cell Experiment | |
|---|---|
| Cell lines | Rat1-myr-p110α, β, and δ and TSC1−/−-null MEFs cells |
| Preparation method | A total of 2 × 106 cells were seeded per 10-cm dish. Eighteen hours later, the medium was discarded and replaced with 10 mL of fresh medium containing the test items. Unless specified in the figure legend, the incubation period was 30 minutes. For agonist activation, cells were first starved for 18 hours in 9 mL of medium containing only 0.05% FBS. Then cells were pretreated for 30 minutes by addition of 1 mL of medium containing the test items and subsequently stimulated for 10 minutes with the agonist (final concentrations: 50 ng/mL for PDGF, 100 ng/mL for epidermal growth factor (EGF), 60 ng/mL interleukin (IL)-4, and 1 μmol/L anisomycin). Cells were washed twice, lysed, and processed by Western blot analysis as described |
| Concentrations | 0~10µM |
| Incubation time | 30 min |
| Animal Experiment | |
|---|---|
| Animal models | Orthotopic BT-474 tumors model with female Harlan nude (HsdNpa:Athymic Nude-nu) mice (8–10 weeks of age) |
| Formulation | formulated in NMP/PEG300 (10/90, v/v) |
| Dosages | 10 mg/kg |
| Administration | orally |
| Molecular Weight | 410.39 |
| Formula | C18H21F3N6O2 |
| CAS Number | 944396-07-0 |
| Solubility (25°C) | DMSO ≥ 80 mg/mL |
| Storage |
Powder -20°C 3 years ; 4°C 2 years In solvent -80°C 6 months ; -20°C 1 month |
| Species | Mouse | Rat | Rabbit | Guinea pig | Hamster | Dog |
| Weight (kg) | 0.02 | 0.15 | 1.8 | 0.4 | 0.08 | 10 |
| Body Surface Area (m2) | 0.007 | 0.025 | 0.15 | 0.05 | 0.02 | 0.5 |
| Km factor | 3 | 6 | 12 | 8 | 5 | 20 |
| Animal A (mg/kg) = Animal B (mg/kg) multiplied by | Animal B Km |
| Animal A Km |
For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for Compound A of 10 mg/kg.
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SNV4818 is a potential best-in-class (best-in-class) mutation-selective PI3K-α inhibitor with excellent selectivity for the H1047X mutant and moderate selectivity for the related E545/542X mutant. |
| hSMG-1 inhibitor 11j
hSMG-1 inhibitor 11j, a pyrimidine derivative, is a potent and selective inhibitor of hSMG-1, with an IC50 of 0.11 nM. |
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PI3Kδ-IN-13 is a PI3Kδ inhibitor (IC50=2.6 nM). |
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