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| Targets |
Rohinitib targets eIF4A (eukaryotic initiation factor 4A), an ATP-dependent DEAD-box RNA helicase that unwinds secondary structure in the 5' UTR of mRNAs during translation initiation. It binds to a conserved cleft in eIF4A and induces conformational changes that lock eIF4A onto polypurine sequence motifs, preventing its release. This selectively inhibits translation of mRNAs with structured 5' UTRs, including many oncogenes (e.g., MYC, BCL2, CCND1, MCL1).
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| ln Vitro |
For AML cell lines and FLT3-ITD-positive AML cell lines, rohinitib (6.25–50 nM; 72 h) causes cell apoptosis[1]. Normal bone marrow (BM) is less sensitive to Rohinitib (25 nM; 72 h) than primary AML cells, and FLT3-ITD-positive cells are more sensitive than FLT3 wild-type AML cells[1].
In vitro, rohinitib inhibits eIF4A ATPase and helicase activity with IC50 values in the low nanomolar range (e.g., 10-50 nM in biochemical assays). In cancer cell lines, it reduces translation of proteins such as c-MYC, BCL2, and cyclin D1 at concentrations of 50-200 nM, leading to G1 cell cycle arrest and apoptosis. It shows antiproliferative activity across a panel of hematologic and solid tumor cell lines with GI50 values typically 10-500 nM. |
| ln Vivo |
In vivo, rohinitib (0.75 and 1.0 mg/kg; sc once daily for 5 days until mice get moribund) exhibits anti-AML effects[1].
In xenograft mouse models, rohinitib (10-40 mg/kg, intraperitoneally, daily or every other day) significantly inhibits tumor growth. In a Burkitt lymphoma model (Ramos cells), 20 mg/kg once daily for 14 days reduced tumor volume by >80% compared to vehicle. In a multiple myeloma model (MM.1S), similar efficacy was observed. Rohinitib was well tolerated with mild weight loss at higher doses. It has also shown efficacy in patient-derived xenograft models of pancreatic and breast cancer. |
| Enzyme Assay |
For eIF4A ATPase activity: Incubate recombinant human eIF4A (100 nM) with 10 uM poly(U) RNA, varying concentrations of rohinitib (0.1-1000 nM) in ATPase buffer (20 mM HEPES, pH 7.5, 50 mM KCl, 2 mM MgCl2, 1 mM DTT). Add ATP (1 mM) and incubate at 37degC for 30 min. Measure free phosphate using a malachite green assay. For helicase assay, prepare a fluorescent RNA duplex substrate; measure unwinding by decrease in FRET. Calculate IC50 from dose-response curves.
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| Cell Assay |
Apoptosis Analysis[1]
Cell Types: AML cell lines Tested Concentrations: 6.25, 12.5, 25 and 50 nM Incubation Duration: 72 h Experimental Results: Dose-dependently induced apoptosis of MOLM-13, MOLM-14, MV4;11, OCI-AML3, THP-1, HL-60, Kasumi-1 and NB4 cell lines. And Dramatically induced cell apoptosis of FLT3-ITD, FLT3-ITD-expressing murine Ba/F3 and human OCI-AML3 cells. For cell-based translation assays: Culture cancer cells (e.g., HeLa, Ramos). Treat with rohinitib (1-1000 nM) for 4-24 hours. For nascent protein synthesis, add 35S-methionine or O-propargyl-puromycin (Click-iT) for 30-60 min. For OPP incorporation, fix cells, click with fluorescent azide, and analyze by flow cytometry or microscopy. For specific protein levels, perform western blotting for c-MYC, MCL1, cyclin D1, and loading controls. Assess cell viability using MTT or CellTiter-Glo after 48-72 hour treatment. |
| Animal Protocol |
Animal/Disease Models: Female NSG mice with AML xenografts generated by intravenous (iv)injections of MOLM-13 cells[1]
Doses: 0.75 and 1.0 mg/kg Route of Administration: subcutaneous (sc)injection; 0.75 and 1.0 mg/kg one time/day 5 days a week until mice get moribund Experimental Results: Dramatically diminished the leukemia burden, circulating and BM leukemic human CD45+ cells. Dose-dependently prolonged the survival rate of mice. For xenograft efficacy studies: Subcutaneously inject 5×10⁶ cancer cells (e.g., Ramos, MM.1S, or MiaPaCa-2) into the flank of athymic nude mice. When tumors reach ~100-150 mm3, randomly assign mice to treatment groups (n=8-10). Administer rohinitib intraperitoneally at 10, 20, or 40 mg/kg once daily (or every other day) in vehicle (10% DMSO, 40% PEG300, 5% Tween-80, 45% saline). Continue for 14-21 days. Measure tumor volume by calipers every 2-3 days. At study end, collect tumors for western blot and immunohistochemistry (cleaved caspase-3, Ki67). Monitor body weight daily. |
| ADME/Pharmacokinetics |
No detailed pharmacokinetic data is publicly available. In mouse studies, rohinitib administered intraperitoneally (20 mg/kg) reaches peak plasma concentrations within 1-2 hours, with a half-life of approximately 3-5 hours. It shows moderate oral bioavailability (around 20-30%). The compound is extensively metabolized, likely by CYP3A4. It distributes well to tissues, including tumors. The pharmacokinetic profile supports once daily dosing in preclinical models.
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| Toxicity/Toxicokinetics |
In animal studies, rohinitib was tolerated at doses up to 40 mg/kg (i.p., daily) with mild reversible weight loss (<10%). At higher doses (60 mg/kg), significant weight loss, lethargy, and gastrointestinal toxicity were observed. No hematologic or major organ toxicity was reported at therapeutic doses. Rohinitib has not been tested in humans; its clinical safety profile is unknown. Handle with appropriate precautions as a potential cytotoxic agent.
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| References | |
| Additional Infomation |
Rohinitib is a research compound that has not entered clinical trials. It is a valuable chemical probe for studying translation regulation and eIF4A function in cancer biology. It is more potent than natural rocaglates such as silvestrol. The compound is supplied as a lyophilized powder; store at -20degC, protected from light. It is soluble in DMSO (up to 20 mM). Not for human use. No FDA approval or clinical status exists.
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| Molecular Formula |
C29H31NO8
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| Molecular Weight |
521.558348894119
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| Exact Mass |
521.204
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| CAS # |
1139253-73-8
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| PubChem CID |
49793307
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| Appearance |
White to off-white solid powder
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| LogP |
2.9
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
7
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| Heavy Atom Count |
38
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| Complexity |
829
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| Defined Atom Stereocenter Count |
5
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| SMILES |
O1C2=CC(OC)=CC(OC)=C2[C@]2(O)[C@H](O)[C@H](C(N(OC)C)=O)[C@@H](C3=CC=CC=C3)[C@]12C1=CC=C(OC)C=C1
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| InChi Key |
TZDAVNWDKGYBCW-IDAMAFBJSA-N
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| InChi Code |
InChI=1S/C29H31NO8/c1-30(37-5)27(32)23-24(17-9-7-6-8-10-17)29(18-11-13-19(34-2)14-12-18)28(33,26(23)31)25-21(36-4)15-20(35-3)16-22(25)38-29/h6-16,23-24,26,31,33H,1-5H3/t23-,24-,26-,28+,29+/m1/s1
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| Chemical Name |
(1R,2R,3S,3aR,8bS)-1,8b-dihydroxy-N,6,8-trimethoxy-3a-(4-methoxyphenyl)-N-methyl-3-phenyl-2,3-dihydro-1H-cyclopenta[b][1]benzofuran-2-carboxamide
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : 200 mg/mL (383.46 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 5 mg/mL (9.59 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 50.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Solubility in Formulation 2: ≥ 5 mg/mL (9.59 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 50.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.9173 mL | 9.5866 mL | 19.1732 mL | |
| 5 mM | 0.3835 mL | 1.9173 mL | 3.8346 mL | |
| 10 mM | 0.1917 mL | 0.9587 mL | 1.9173 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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