Synonym
IITZ-01; IITZ 01; IITZ01; Autophagy inhibitor IITZ-01;
IUPAC/Chemical Name
N2-(4-(1H-benzo[d]imidazol-2-yl)phenyl)-N4-(4-fluorophenyl)-6-morpholino-1,3,5-triazine-2,4-diamine
InChi Key
XGEDDGLPNSLBFE-UHFFFAOYSA-N
InChi Code
InChI=1S/C26H23FN8O/c27-18-7-11-20(12-8-18)29-25-32-24(33-26(34-25)35-13-15-36-16-14-35)28-19-9-5-17(6-10-19)23-30-21-3-1-2-4-22(21)31-23/h1-12H,13-16H2,(H,30,31)(H2,28,29,32,33,34)
SMILES Code
FC1=CC=C(NC2=NC(N3CCOCC3)=NC(NC4=CC=C(C5=NC6=CC=CC=C6N5)C=C4)=N2)C=C1
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
Shelf Life
>3 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
Autophagy is a homeostatic process that recycles damaged organelles and long-lived proteins by delivering them in double-membrane vesicles to lysosomes for degradation. Autophagy has a prominent role in survival, proliferation, and resistance of tumors in metabolic and chemotherapeutic stress conditions. Clinical trials with chloroquine-a known autophagy inhibitor-were unable to achieve complete autophagy inhibition in vivo, warranting the search for more potent autophagy inhibitors
Biological target:
IITZ-01 is a potent lysosomotropic autophagy inhibitor with single-agent antitumor activity, with an IC50 of 2.62 μM for PI3Kγ.
In vitro activity:
Sub-lethal concentrations of a lysosomotropic autophagy inhibitor, IITZ-01, sensitizes cancer cells (renal, lung, and breast carcinoma) to TRAIL-induced apoptosis through DR5 upregulation and survivin downregulation through ubiquitin-proteasome pathway. Knockdown of DR5 or overexpression of survivin inhibited combined treatment with IITZ-01 and TRAIL-induced apoptosis. IITZ-01 downregulated protein expression of Cbl, ubiquitin E3 ligase, and decreased expression level of Cbl markedly led to increase DR5 protein expression and TRAIL sensitivity. Moreover, IITZ-01 decreased expression level of survivin protein via downregulation of deubiquitinase ubiquitin-specific protease 9X (USP9X) expression. Taken together, these results provide the first evidence that IITZ-01 enhances TRAIL-mediated apoptosis through DR5 stabilization by downregulation of Cbl and USP9X-dependent survivin ubiquitination and degradation in renal carcinoma cells.
Reference: Cancers (Basel). 2020 Aug 21;12(9):2363. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/32825566/
In vivo activity:
The antitumor efficacy of IITZ-01 was investigated in in-vivo breast cancer model. MDA-MB-231/green fluorescent protein (GFP) orthotropic breast cancer xenografts were developed in CrTac:NCr-Foxnnu BALB/c female nude mice. Tumors after reaching ~100 mm3, vehicle, 45 mg/kg of IITZ-02, were administered through intraperitoneal (i.p.) route on every alternate day for 4 weeks. IITZ-01 reduced the active tumor burden around 8.8-fold when compared with control group as determined by tumor photon counts. Moreover, tumor volume measurements have demonstrated that IITZ-01 significantly inhibited average tumor growth when compared with control from third day of treatment (Fig. 7a–c). Significant reduction in average tumor weights was observed after treatment with test compounds compared with control (Fig. 7d). This treatment schedule of both compounds was well tolerated in mice for the total duration of administration with no significant changes in their body weights (Fig. 7e). In addition, hematoxylin and eosin staining revealed large areas of necrosis in treated groups of both compounds when compared with controls. Immunohistochemistry in histological sections revealed that exposure of both compounds have enhanced LC3-II- and PARP-positive staining in cells than vehicle control, indicating effective autophagy inhibition and triggering of apoptosis (Fig. 7f). Altogether, these findings demonstrated that IITZ-01 inhibits breast tumor growth by autophagy inhibition and apoptosis induction in vivo.
Reference: Oncogene. 2019 Jan;38(4):581-595. https://doi.org/10.1038/s41388-018-0446-2
|
Solvent |
mg/mL |
mM |
| Solubility |
| DMSO |
100.0 |
207.24 |
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
482.52
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. Shahriyar SA, Seo SU, Min KJ, Kubatka P, Min DS, Chang JS, Kim DE, Woo SM, Kwon TK. Upregulation of DR5 and Downregulation of Survivin by IITZ-01, Lysosomotropic Autophagy Inhibitor, Potentiates TRAIL-Mediated Apoptosis in Renal Cancer Cells via Ubiquitin-Proteasome Pathway. Cancers (Basel). 2020 Aug 21;12(9):2363. doi: 10.3390/cancers12092363. PMID: 32825566; PMCID: PMC7564912.
2. Guntuku L, Gangasani JK, Thummuri D, Borkar RM, Manavathi B, Ragampeta S, Vaidya JR, Sistla R, Vegi NGM. IITZ-01, a novel potent lysosomotropic autophagy inhibitor, has single-agent antitumor efficacy in triple-negative breast cancer in vitro and in vivo. Oncogene. 2019 Jan;38(4):581-595. doi: 10.1038/s41388-018-0446-2. Epub 2018 Aug 30. PMID: 30166591.
In vivo protocol:
1. Guntuku L, Gangasani JK, Thummuri D, Borkar RM, Manavathi B, Ragampeta S, Vaidya JR, Sistla R, Vegi NGM. IITZ-01, a novel potent lysosomotropic autophagy inhibitor, has single-agent antitumor efficacy in triple-negative breast cancer in vitro and in vivo. Oncogene. 2019 Jan;38(4):581-595. doi: 10.1038/s41388-018-0446-2. Epub 2018 Aug 30. PMID: 30166591.
1: Shahriyar SA, Seo SU, Min KJ, Kubatka P, Min DS, Chang JS, Kim DE, Woo SM, Kwon TK. Upregulation of DR5 and Downregulation of Survivin by IITZ-01, Lysosomotropic Autophagy Inhibitor, Potentiates TRAIL-Mediated Apoptosis in Renal Cancer Cells via Ubiquitin-Proteasome Pathway. Cancers (Basel). 2020 Aug 21;12(9):2363. doi: 10.3390/cancers12092363. PMID: 32825566; PMCID: PMC7564912.
2: Guntuku L, Gangasani JK, Thummuri D, Borkar RM, Manavathi B, Ragampeta S, Vaidya JR, Sistla R, Vegi NGM. IITZ-01, a novel potent lysosomotropic autophagy inhibitor, has single-agent antitumor efficacy in triple-negative breast cancer in vitro and in vivo. Oncogene. 2019 Jan;38(4):581-595. doi: 10.1038/s41388-018-0446-2. Epub 2018 Aug 30. PMID: 30166591.
