WARNING: This product is for research use only, not for human or veterinary use.
MedKoo CAT#: 205923
Description: BAY1082439 is an orally bioavailable inhibitor of the class I phosphoinositide 3-kinase (PI3K) alpha and beta isoforms with potential antineoplastic activity. PI3K alpha/beta inhibitor BAY1082439 selectively inhibits both PI3K alpha, including mutated forms of PIK3CA, and PI3K beta in the PI3K/Akt/mTOR pathway, which may result in tumor cell apoptosis and growth inhibition in PI3K-expressing and/or PTEN-driven tumor cells. By specifically targeting class I PI3K alpha and beta, this agent may be more efficacious and less toxic than pan PI3K inhibitors.
MedKoo Cat#: 205923
Chemical Formula: C25H30N6O5
Exact Mass: 494.2278
Molecular Weight: 494.552
Elemental Analysis: C, 60.72; H, 6.11; N, 16.99; O, 16.18
Synonym: BAY10-82439; BAY 10-82439; BAY-10-82439; BAY1082439; BAY 1082439; BAY-1082439.
IUPAC/Chemical Name: (S)-N-(8-(2-hydroxy-3-morpholinopropoxy)-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-2-methylnicotinamide
InChi Key: JGNRMIWLBBNSMU-KRWDZBQOSA-N
InChi Code: InChI=1S/C25H30N6O5/c1-16-18(4-3-7-26-16)24(33)29-25-28-21-19(23-27-8-9-31(23)25)5-6-20(22(21)34-2)36-15-17(32)14-30-10-12-35-13-11-30/h3-7,17,32H,8-15H2,1-2H3,(H,28,29,33)/t17-/m0/s1
SMILES Code: C1=CC(OC[C@@H](O)CN2CCOCC2)=C(OC)C2N=C(NC(=O)C3=CC=CN=C3C)N3CCN=C3C1=2
Appearance: White to off-white solid powder
Purity: >98% (or refer to the Certificate of Analysis)
Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
Solubility: Soluble in DMSO, not in water
Shelf Life: >2 years if stored properly
Drug Formulation: This drug may be formulated in DMSO
Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).
HS Tariff Code: 2934.99.9001
|Biological target:||BAY1082439 is an orally bioavailable, selective PI3Kα/β/δ inhibitor.|
|In vitro activity:||To test whether BAY1082439 (Fig. S1A) could achieve better efficacy by preventing rebound activation of the PI3K pathway, PC3 and LNCaP cells, both PTEN-null human prostate cancer cell lines, were treated with various concentrations of BAY1082439 for 72 hours. BAY1082439 effectively inhibited cell growth (Fig. 1A) by blocking the G1/S cell cycle transition and by inducing apoptosis (Fig. S1B-C). The PI3Kβ-specific inhibitor TGX-221 and the PI3Kα-specific inhibitor BYL-719 were significantly less effective in inhibiting cell growth and blocking the G1 to S transition (Fig. 1A; Fig. S1C). In isogenic PC3 PTEN-WT and PTEN-null cells, PTEN-null cells were three orders of magnitude more sensitive to BAY1082439 than WT cells (Fig. 1B), indicating a wide, PTEN status-dependent therapeutic window. In both human prostate cancer cell lines and the CaP8 and CaP2 cell lines derived from the CP mice, BAY1082439 prevented the feedback activation of the PI3K pathway and the rebound AKT phosphorylation seen with TGX-221 treatment (Fig. 1C and Fig. 1D), and demonstrated equal potency to inhibit cell growth as the combination of the PI3Kα and PI3Kβ inhibitors TGX-221 and BYL-719 (Fig. 1E). Reference: Mol Cancer Ther. 2018 Oct;17(10):2091-2099. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/30045927/|
|In vivo activity:||Based on the superior and sustainable activity of BAY1082439 to inhibit AKT phosphorylation of human and mouse PTEN-null prostate cancer lines (Fig. 1C-D), the effect of BAY1082439 was tested in vivo. CP mice were treated with 75 mg/kg of BAY1082439 daily, starting at 6 weeks when PINs form, and ending at 10 weeks when untreated tumors progress to localized adenocarcinoma (Fig. 2A). BAY1082439 was well tolerated over the course of the study (Fig. S2). In comparison to the vehicle controls, the BAY1082439 treatment group showed significantly decreased tumor size and P-AKT staining, nearly normal luminal architecture (Fig. 2B; Fig. S3A), and a significant reduction of Ki67-positive cells (Fig. 2C). Smooth muscle actin (SMA) staining indicated no local invasion in the BAY1082439 treatment group compared to vehicle controls (Fig. S3B). We also tested the effect of BAY1082439 on PC3 xenograft tumors in vivo, which harbors PTEN and P53 mutations. BAY1082439 can significantly inhibit the human prostate cancer growth as compared to vehicle controls (Fig. 2D). Together, these results showed that BAY1082439 effectively prevented prostate cancer progression in the clinically relevant CP model and inhibit aggressive human prostate cancer cell growth in vivo. Reference: Mol Cancer Ther. 2018 Oct;17(10):2091-2099. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/30045927/|
|Solvent||Max Conc. mg/mL||Max Conc. mM|
The following data is based on the product molecular weight 494.552 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.
|Concentration / Solvent Volume / Mass||1 mg||5 mg||10 mg|
|1 mM||1.15 mL||5.76 mL||11.51 mL|
|5 mM||0.23 mL||1.15 mL||2.3 mL|
|10 mM||0.12 mL||0.58 mL||1.15 mL|
|50 mM||0.02 mL||0.12 mL||0.23 mL|
|In vitro protocol:||1. Zou Y, Qi Z, Guo W, Zhang L, Ruscetti M, Shenoy T, Liu N, Wu H. Cotargeting the Cell-Intrinsic and Microenvironment Pathways of Prostate Cancer by PI3Kα/β/δ Inhibitor BAY1082439. Mol Cancer Ther. 2018 Oct;17(10):2091-2099. doi: 10.1158/1535-7163.MCT-18-0038. Epub 2018 Jul 25. PMID: 30045927; PMCID: PMC6168338.|
|In vivo protocol:||1. Zou Y, Qi Z, Guo W, Zhang L, Ruscetti M, Shenoy T, Liu N, Wu H. Cotargeting the Cell-Intrinsic and Microenvironment Pathways of Prostate Cancer by PI3Kα/β/δ Inhibitor BAY1082439. Mol Cancer Ther. 2018 Oct;17(10):2091-2099. doi: 10.1158/1535-7163.MCT-18-0038. Epub 2018 Jul 25. PMID: 30045927; PMCID: PMC6168338.|
BAY1082439 is a highly selective PI3Kα/α-balanced inhibitor. BAY 1082439 represents a new type of PI3K inhibitor with unique pharmacological and pharmacodynamic properties. BAY 1082439 has an IC50 ratio of 1:3 in biochemical assays of PI3Kα (4.9 nM) vs. PI3Kα (15.0 nM), and >1000-fold selectivity against mTOR kinase. In vivo, BAY 1082439 showed clear advantages over the strong PI3Kα inhibitor BAY 80-6946 in PTEN/PI3Kα-driven tumor models (e.g., PC3 and HEC-1B), when the two compounds were compared at their MTDs. Furthermore, BAY 1082439 has unique pharmacokinetic (PK) properties with very high plasma free fractions across all species tested (33-50%), large Vss, high clearance and intermediate T1/2. BAY 1082439 showed strong p-AKT inhibition at 2 and 5 hours post-treatment while p-AKT returned to levels comparable to the vehicle group at 24 hours in all 4 tumor models tested. Interestingly, with once daily dosing, BAY 1082439 could induce tumor regression in KPL4 (PIK3CAmut and HER2+), and tumor stasis in HEC-1B (PTENdel) and in HEC-1A (PIK3CAmut) tumor models. (source: Cancer Research: April 15, 2012; Volume 72, Issue 8, Supplement 1 doi: 10.1158/1538-7445.AM2012-2799. Proceedings: AACR 103rd Annual Meeting 2012-- Mar 31-Apr 4, 2012; Chicago, IL )