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Purity: ≥98%
DT-061 (also known as DT061; SMAP) is a novel, potent and orally bioavailable activator of PP2A (protein phosphatase 2A) with anticancer effects. It could be applied in the therapy of KRAS-mutant and MYC-driven tumorigenesis. Treatment with DT-061, in combination with the MEK inhibitor AZD6244, resulted in suppression of both p-AKT and MYC, as well as tumor regression in two KRAS-driven lung cancer mouse models. DT-061 therapy also abrogated MYC-driven tumorigenesis.
| Targets |
PP2A[1].
DT-061 directly binds to the scaffolding A subunit of protein phosphatase 2A (PP2A), specifically PPP2R1A, acting as a small-molecule activator of PP2A (SMAP) [1] |
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| ln Vitro |
DT-061 showed a sensitivity profile in KRAS-mutant lung cancer cell lines overexpressing PP2A inhibitory proteins (PIPs), similar to cells with a PPP2R1A E64D mutation [1]
CIP2A overexpression did not confer further resistance to DT-061 [1] In KRAS-mutant H358 and H441 cell lines, DT-061 showed dose-dependent inhibition of colony growth as a single agent [1] DT-061 in combination with the MEK inhibitor AZD6244 (at concentrations that alone did not affect colony growth) resulted in very apparent combinatorial growth inhibition in H358 and H441 cells [1] DT-061 treatment induced a dose-dependent activation of caspase-3/7 in H358 and H441 cells at a 24-hour time point, while AZD6244 alone did not [1] When both drugs were used at 10 µM, DT-061 enhanced the apoptosis response in H358 and H441 cells [1] The combination of DT-061 and MEK inhibitor potently inhibited p-AKT and MYC expression in KRAS-mutant lung cancer cell lines H358 and H441 [1] DT-061 inhibits AKT and RPS6K signaling in H358 cells [1] |
| ln Vivo |
DT-061 (5 mg/kg, oral gavage, 4 weeks) inhibits the growth of H358 or H441 xenografts as a single agent. Furthermore, there is a considerable increase in efficiency when DT-061 and AZD6244 are combined[1].
The capacity of DT-061 to inhibit H358 xenograft growth was dependent on drug binding to PPP2R1A [1] In H358 xenograft models, both DT-061 and AZD6244 showed single-agent activity in inhibiting tumor volume, but their combination was significantly more efficient than either compound alone [1] Similar results were obtained in H441 xenograft models, where the combination of DT-061 and AZD6244 was significantly more efficient than monotherapies [1] Based on RECIST criteria, most mice treated with DT-061 alone had progressive disease, while all mice treated with the combination of DT-061 and AZD6244 showed at least a partial response; one H358 xenograft showed a complete response [1] The combination of DT-061 and AZD6244 had an additive effect on reducing tumor cell proliferation (measured by PCNA-positive cells) and increasing apoptosis (measured by TUNEL-positive cells) in tumor tissue [1] DT-061 combined with AZD6244 inhibited endogenous MYC expression in drug-treated tumors in vivo [1] In H358-GFP control xenografts, DT-061 monotherapy (5 mg/kg) inhibited tumor growth over a 20-day period, with an effect comparable to the combination of AZD6244 and the AKT inhibitor MK2206 [1] In H358 xenografts overexpressing wild-type MYC, DT-061 monotherapy (5 mg/kg) inhibited tumor growth to a similar extent as the AZD6244+MK2206 combination [1] In H358 xenografts overexpressing a MYC mutant (S62D) resistant to PP2A-mediated degradation, DT-061 monotherapy (5 mg/kg) induced only partial tumor growth inhibition, whereas the AZD6244+MK2206 combination remained efficient [1] |
| Cell Assay |
For colony formation assays involving DT-061 and AZD6244, cells (H358, H441) were seeded at 1000 cells per well and allowed to grow for 3 weeks in the presence of vehicle control or increasing concentrations of the drugs. Cells were then fixed, stained with crystal violet, and quantified [1]
For cell viability assays, cells were plated in 96-well plates. After incubation for 24 hours, cultures were treated with drugs for 3 days. The proportion of viable cells was determined by WST1 assay according to the manufacturer's recommendations [1] For apoptosis assays (Caspase-3/7 activity), cells were plated in 96-well plates. After incubation for 24 hours, cultures were treated with drugs. Caspase-3/7 activity was determined using a Caspase-Glo 3/7 Assay according to the manufacturer's recommendations [1] For Western blot analysis to assess signaling pathways (e.g., p-AKT, MYC), cells were treated with drugs, lysed, and proteins were analyzed using standard immunoblotting techniques [1] |
| Animal Protocol |
Animal/Disease Models: 6 - to 8weeks old male BALB/c nu/nu (nude) mice injected with H441 cells (5 × 106)[1].
Doses: 5 mg/kg. Route of Administration: po (oral gavage) for 4 weeks. Experimental Results: demonstrated activity in inhibiting tumor growth. For xenograft studies, H358 (1 × 10⁷ cells) or H441 (5 × 10⁶ cells) were injected subcutaneously into the right flank of 6- to 8-week-old male BALB/c nu/nu mice [1] When tumor volumes reached an average of 100 mm³, mice were randomized to treatment groups [1] Mice were treated by oral gavage with vehicle control, AZD6244 (25 mg/kg), DT-061 (5 mg/kg), or DT-061 in combination with AZD6244 [1] Tumor volume was assessed by caliper measurement every other day [1] Body weights were recorded weekly [1] Animals were observed for signs of toxicity (mucous diarrhea, abdominal stiffness, or weight loss) [1] Blood and tumor tissue were harvested 2 hours after the final dose [1] |
| References | |
| Additional Infomation |
DT-061 is a small molecule PP2A (SMAP) activator with high oral bioavailability and is also a modified derivative of tricyclic antipsychotic drugs [1]. Mutations at the putative DT-061 target binding site on PPP2R1A or overexpression of the viral PIP SV40 small t antigen would eliminate its anticancer activity [1]. DT-061 is believed to be able to change the response of MEK inhibitors in KRAS mutant cells from cytotoxicity to cytotoxicity [1].
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| Molecular Formula |
C25H23F3N2O5S
|
|---|---|
| Molecular Weight |
520.5207
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| Exact Mass |
520.127
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| CAS # |
1809427-19-7
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| Related CAS # |
(1S,2S,3R)-DT-061;1809427-20-0
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| PubChem CID |
91885558
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| Appearance |
Off-white to light yellow solid powder
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| LogP |
5.4
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| Hydrogen Bond Donor Count |
2
|
| Hydrogen Bond Acceptor Count |
10
|
| Rotatable Bond Count |
5
|
| Heavy Atom Count |
36
|
| Complexity |
824
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| Defined Atom Stereocenter Count |
3
|
| SMILES |
S(C1C([H])=C([H])C(=C([H])C=1[H])OC(F)(F)F)(N([H])[C@]1([H])C([H])([H])C([H])([H])C([H])([H])[C@@]([H])([C@@]1([H])O[H])N1C2=C([H])C([H])=C([H])C([H])=C2OC2=C([H])C([H])=C([H])C([H])=C12)(=O)=O
|
| InChi Key |
WGKGADVPRVLHHZ-ZHRMCQFGSA-N
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| InChi Code |
InChI=1S/C25H23F3N2O5S/c26-25(27,28)35-16-12-14-17(15-13-16)36(32,33)29-18-6-5-9-21(24(18)31)30-19-7-1-3-10-22(19)34-23-11-4-2-8-20(23)30/h1-4,7-8,10-15,18,21,24,29,31H,5-6,9H2/t18-,21+,24+/m1/s1
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| Chemical Name |
N-((1R,2R,3S)-2-hydroxy-3-(10H-phenoxazin-10-yl)cyclohexyl)-4-(trifluoromethoxy)benzenesulfonamide
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| Synonyms |
DT 061; DT61; SMAP; DT-061; DT061; DT-61; DT 61
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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 : ~125 mg/mL (~240.14 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (4.00 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% 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 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: 2.08 mg/mL (4.00 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 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. View More
Solubility in Formulation 3: ≥ 2.08 mg/mL (4.00 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.9212 mL | 9.6058 mL | 19.2116 mL | |
| 5 mM | 0.3842 mL | 1.9212 mL | 3.8423 mL | |
| 10 mM | 0.1921 mL | 0.9606 mL | 1.9212 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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