Dactolisib | BEZ235 | CAS# 915019-65-7 | PI3K inhibitor

MedKoo Cat#: 200491 | Name: Dactolisib

Description:

WARNING: This product is for research use only, not for human or veterinary use.

Dactolisib, also known as BEZ235, is an orally bioavailable phosphatidylinositol 3-kinase (PI3K) inhibitor with potential antineoplastic activity. PI3K inhibitor BEZ235 specifically inhibits PIK3 in the PI3K/AKT kinase (or protein kinase B) signaling pathway, which may trigger the translocation of cytosolic Bax to the mitochondrial outer membrane, increasing mitochondrial membrane permeability; apoptotic cell death may ensue. Bax is a member of the proapoptotic Bcl2 family of proteins.

Chemical Structure

Dactolisib

CAS#915019-65-7 (free base)

Theoretical Analysis

MedKoo Cat#: 200491

Name: Dactolisib

CAS#: 915019-65-7 (free base)

Chemical Formula: C30H23N5O

Exact Mass: 469.1903

Molecular Weight: 469.54

Elemental Analysis: C, 76.74; H, 4.94; N, 14.92; O, 3.41

Price and Availability

Size	Price	Availability
50mg	USD 90.00	Ready to ship
100mg	USD 150.00	Ready to ship
200mg	USD 250.00	Ready to ship
500mg	USD 550.00	Ready to ship
1g	USD 950.00	Ready to ship

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Related CAS #

1028385-32-1 (tosylate) 915019-65-7 (free base) 2319647-83-9 (HCl)

Synonym

BEZ235; BEZ-235; BEZ 235; NVPBEZ235; NVP-BEZ235; NVP-BEZ-235; NVP-BEZ 235; Dactolisib.

IUPAC/Chemical Name

2-Methyl-2-[4-[3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydroimidazo[4,5-c]quinolin-1-yl]phenyl]propionitrile.

InChi Key

JOGKUKXHTYWRGZ-UHFFFAOYSA-N

InChi Code

InChI=1S/C30H23N5O/c1-30(2,18-31)22-9-11-23(12-10-22)35-28-24-15-19(21-14-20-6-4-5-7-25(20)32-16-21)8-13-26(24)33-17-27(28)34(3)29(35)36/h4-17H,1-3H3

SMILES Code

CC(C1=CC=C(N(C2=C3C=NC4=CC=C(C5=CC6=CC=CC=C6N=C5)C=C24)C(N3C)=O)C=C1)(C)C#N

Appearance

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

More Info

BEZ235 is a dual phosphatidylinositol 3-kinase (PI(3)K)/mammalian target of rapamycin (mTOR) inhibitor that is orally available and that has been shown to be effective in several malignancies in vitro. Recently, BEZ235 entered clinical trials for solid tumors.

Product Data

Product Data

Certificate of Analysis

View CoA: current batch, Lot# C9R11B26

QC Data

View QC data: current batch, Lot# C9R11B26

Safety Data Sheet (SDS)

View Safety Data Sheet (SDS)

Instruction

View handling instruction

Biological target:

Dactolisib (BEZ235) is a dual pan-class I PI3K and mTOR kinase inhibitor with IC50s of 4 nM/5 nM/7 nM/75 nM, and 20.7 nM for p110α/p110γ/p110δ/p110β and mTOR, respectively.

In vitro activity:

BEZ235 reduced cell viability in a dose-dependent manner, as shown by CCK8 assays (Figure 1A). The IC50 values of BEZ235 for HL-60/VCR and K562/ADR cells were 66.69 nmol/L and 71.44 nmol/L, respectively. After treatment with different concentrations of BEZ235 for 24 h, the migration of both cell lines significantly decreased (Figure 1B). BEZ235 also induced apoptosis in the HL-60/VCR and K562/ADR cells in a dose-dependent manner (Figure 1C). Reference: Acta Pharmacol Sin. 2017 Mar; 38(3): 382–391. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5342661/

In vivo activity:

Subsequently, the peeled tumors were subjected to paraffin embedded sections. The protein expressions of p53 and p21 in tumor sections were tested by IHC assays. In both K1 and C643 tumors, p21 expression was higher in NVP-BEZ235 treated mice compared with the controls, since an increased percent and stronger staining of p21 positive cells were observed. While only the mice bearing K1 tumors displayed greater portion and stronger staining of p53 positive cells, rather than C643 tumors. These results suggested a p53-independent mechanism of p21 up-regulation in NVP-BEZ235 treated C643 xenograft tumors, which was consistent with the results of in-vitro studies. Moreover, the mitotic cell marker, Ki67 was shown much weaker in the NVP-BEZ235 treated tumors than the control tumors, further suggested NVP-BEZ235 suppresses thyroid cancer cell proliferation (Figure 7C). Taken together, these results indicated that NVP-BEZ235 treatment inhibited tumor growth in mice injected with K1 cells or C643 cells and substantiate our findings that NVP-BEZ235 inhibits thyroid cancer growth independent of TP53 status. Reference: Int J Biol Sci. 2020; 16(4): 682–693. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6990918/

	Solvent	mg/mL	mM
Solubility
	DMSO	3.0	6.39
	DMF	2.0	4.26
	4-methylpyridine	3.0	6.39

Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.

Preparing Stock Solutions

The following data is based on the product molecular weight 469.54 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

Formulation protocol:

1. Cai J, Xia J, Zou J, Wang Q, Ma Q, Sun R, Liao H, Xu L, Wang D, Guo X. The PI3K/mTOR dual inhibitor NVP-BEZ235 stimulates mutant p53 degradation to exert anti-tumor effects on triple-negative breast cancer cells. FEBS Open Bio. 2020 Apr;10(4):535-545. doi: 10.1002/2211-5463.12806. Epub 2020 Mar 6. PMID: 32027103; PMCID: PMC7137801. 2. Deng L, Jiang L, Lin XH, Tseng KF, Liu Y, Zhang X, Dong RH, Lu ZG, Wang XJ. The PI3K/mTOR dual inhibitor BEZ235 suppresses proliferation and migration and reverses multidrug resistance in acute myeloid leukemia. Acta Pharmacol Sin. 2017 Mar;38(3):382-391. doi: 10.1038/aps.2016.121. Epub 2017 Jan 2. PMID: 28042875; PMCID: PMC5342661. 3. Ruan B, Liu W, Chen P, Cui R, Li Y, Ji M, Hou P, Yang Q. NVP-BEZ235 inhibits thyroid cancer growth by p53- dependent/independent p21 upregulation. Int J Biol Sci. 2020 Jan 14;16(4):682-693. doi: 10.7150/ijbs.37592. PMID: 32025215; PMCID: PMC6990918. 4. Shi F, Zhang J, Liu H, Wu L, Jiang H, Wu Q, Liu T, Lou M, Wu H. The dual PI3K/mTOR inhibitor dactolisib elicits anti-tumor activity in vitro and in vivo. Oncotarget. 2017 Dec 9;9(1):706-717. doi: 10.18632/oncotarget.23091. Erratum in: Oncotarget. 2018 Mar 30;9(24):17255. PMID: 29416647; PMCID: PMC5787502.

In vitro protocol:

In vivo protocol:

1. Ruan B, Liu W, Chen P, Cui R, Li Y, Ji M, Hou P, Yang Q. NVP-BEZ235 inhibits thyroid cancer growth by p53- dependent/independent p21 upregulation. Int J Biol Sci. 2020 Jan 14;16(4):682-693. doi: 10.7150/ijbs.37592. PMID: 32025215; PMCID: PMC6990918. 2. Shi F, Zhang J, Liu H, Wu L, Jiang H, Wu Q, Liu T, Lou M, Wu H. The dual PI3K/mTOR inhibitor dactolisib elicits anti-tumor activity in vitro and in vivo. Oncotarget. 2017 Dec 9;9(1):706-717. doi: 10.18632/oncotarget.23091. Erratum in: Oncotarget. 2018 Mar 30;9(24):17255. PMID: 29416647; PMCID: PMC5787502.

1: Witteck L, Jaster R. Trametinib and dactolisib but not regorafenib exert antiproliferative effects on rat pancreatic stellate cells. Hepatobiliary Pancreat Dis Int. 2015 Dec;14(6):642-50. PubMed PMID: 26663013. 2: Netland IA, Førde HE, Sleire L, Leiss L, Rahman MA, Skeie BS, Gjerde CH, Enger PØ, Goplen D. Dactolisib (NVP-BEZ235) toxicity in murine brain tumour models. BMC Cancer. 2016 Aug 19;16:657. doi: 10.1186/s12885-016-2712-4. PubMed PMID: 27542970; PubMed Central PMCID: PMC4992256. 3: Choudhary GS, Al-Harbi S, Mazumder S, Hill BT, Smith MR, Bodo J, Hsi ED, Almasan A. MCL-1 and BCL-xL-dependent resistance to the BCL-2 inhibitor ABT-199 can be overcome by preventing PI3K/AKT/mTOR activation in lymphoid malignancies. Cell Death Dis. 2015 Jan 15;6:e1593. doi: 10.1038/cddis.2014.525. PubMed PMID: 25590803; PubMed Central PMCID: PMC4669737. 4: Bellozi PM, Lima IV, Dória JG, Vieira ÉL, Campos AC, Candelario-Jalil E, Reis HJ, Teixeira AL, Ribeiro FM, de Oliveira AC. Neuroprotective effects of the anticancer drug NVP-BEZ235 (dactolisib) on amyloid-β 1-42 induced neurotoxicity and memory impairment. Sci Rep. 2016 May 4;6:25226. doi: 10.1038/srep25226. PubMed PMID: 27142962; PubMed Central PMCID: PMC4855228. 5: Han L, Qiu P, Zeng Z, Jorgensen JL, Mak DH, Burks JK, Schober W, McQueen TJ, Cortes J, Tanner SD, Roboz GJ, Kantarjian HM, Kornblau SM, Guzman ML, Andreeff M, Konopleva M. Single-cell mass cytometry reveals intracellular survival/proliferative signaling in FLT3-ITD-mutated AML stem/progenitor cells. Cytometry A. 2015 Apr;87(4):346-56. doi: 10.1002/cyto.a.22628. Epub 2015 Jan 16. PubMed PMID: 25598437; PubMed Central PMCID: PMC4388314. 6: Kiyuna T, Murakami T, Tome Y, Kawaguchi K, Igarashi K, Zhang Y, Zhao M, Li Y, Bouvet M, Kanaya F, Singh A, Dry S, Eilber FC, Hoffman RM. High efficacy of tumor-targeting Salmonella typhimurium A1-R on a doxorubicin- and dactolisib-resistant follicular dendritic-cell sarcoma in a patient-derived orthotopic xenograft PDOX nude mouse model. Oncotarget. 2016 May 31;7(22):33046-54. doi: 10.18632/oncotarget.8848. PubMed PMID: 27105519; PubMed Central PMCID: PMC5078074. 7: Yu Z, Xie G, Zhou G, Cheng Y, Zhang G, Yao G, Chen Y, Li Y, Zhao G. NVP-BEZ235, a novel dual PI3K-mTOR inhibitor displays anti-glioma activity and reduces chemoresistance to temozolomide in human glioma cells. Cancer Lett. 2015 Oct 10;367(1):58-68. doi: 10.1016/j.canlet.2015.07.007. Epub 2015 Jul 15. PubMed PMID: 26188279. 8: Soares HP, Ming M, Mellon M, Young SH, Han L, Sinnet-Smith J, Rozengurt E. Dual PI3K/mTOR Inhibitors Induce Rapid Overactivation of the MEK/ERK Pathway in Human Pancreatic Cancer Cells through Suppression of mTORC2. Mol Cancer Ther. 2015 Apr;14(4):1014-23. doi: 10.1158/1535-7163.MCT-14-0669. Epub 2015 Feb 11. PubMed PMID: 25673820; PubMed Central PMCID: PMC4394038. 9: Vandamme T, Beyens M, de Beeck KO, Dogan F, van Koetsveld PM, Pauwels P, Mortier G, Vangestel C, de Herder W, Van Camp G, Peeters M, Hofland LJ. Long-term acquired everolimus resistance in pancreatic neuroendocrine tumours can be overcome with novel PI3K-AKT-mTOR inhibitors. Br J Cancer. 2016 Mar 15;114(6):650-8. doi: 10.1038/bjc.2016.25. PubMed PMID: 26978006; PubMed Central PMCID: PMC4800296. 10: Kato M, Banuelos CA, Imamura Y, Leung JK, Caley DP, Wang J, Mawji NR, Sadar MD. Cotargeting Androgen Receptor Splice Variants and mTOR Signaling Pathway for the Treatment of Castration-Resistant Prostate Cancer. Clin Cancer Res. 2016 Jun 1;22(11):2744-54. doi: 10.1158/1078-0432.CCR-15-2119. Epub 2015 Dec 28. PubMed PMID: 26712685; PubMed Central PMCID: PMC4891302. 11: Pan CX, Zhang H, Tepper CG, Lin TY, Davis RR, Keck J, Ghosh PM, Gill P, Airhart S, Bult C, Gandara DR, Liu E, de Vere White RW. Development and Characterization of Bladder Cancer Patient-Derived Xenografts for Molecularly Guided Targeted Therapy. PLoS One. 2015 Aug 13;10(8):e0134346. doi: 10.1371/journal.pone.0134346. eCollection 2015. PubMed PMID: 26270481; PubMed Central PMCID: PMC4535951. 12: Boelens MC, Nethe M, Klarenbeek S, de Ruiter JR, Schut E, Bonzanni N, Zeeman AL, Wientjens E, van der Burg E, Wessels L, van Amerongen R, Jonkers J. PTEN Loss in E-Cadherin-Deficient Mouse Mammary Epithelial Cells Rescues Apoptosis and Results in Development of Classical Invasive Lobular Carcinoma. Cell Rep. 2016 Aug 23;16(8):2087-2101. doi: 10.1016/j.celrep.2016.07.059. Epub 2016 Aug 11. PubMed PMID: 27524621; PubMed Central PMCID: PMC4999419. 13: Yu XS, Du J, Fan YJ, Liu FJ, Cao LL, Liang N, Xu DG, Zhang JD. Activation of endoplasmic reticulum stress promotes autophagy and apoptosis and reverses chemoresistance of human small cell lung cancer cells by inhibiting the PI3K/AKT/mTOR signaling pathway. 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Combined treatment by octreotide and everolimus: Octreotide enhances inhibitory effect of everolimus in aggressive meningiomas. J Neurooncol. 2015 Aug;124(1):33-43. doi: 10.1007/s11060-015-1812-3. Epub 2015 May 27. PubMed PMID: 26015296. 20: Miyasaka A, Oda K, Ikeda Y, Sone K, Fukuda T, Inaba K, Makii C, Enomoto A, Hosoya N, Tanikawa M, Uehara Y, Arimoto T, Kuramoto H, Wada-Hiraike O, Miyagawa K, Yano T, Kawana K, Osuga Y, Fujii T. PI3K/mTOR pathway inhibition overcomes radioresistance via suppression of the HIF1-α/VEGF pathway in endometrial cancer. Gynecol Oncol. 2015 Jul;138(1):174-80. doi: 10.1016/j.ygyno.2015.04.015. Epub 2015 Apr 22. PubMed PMID: 25913131.