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| Targets |
SBP-7455 is an orally active dual-specific inhibitor of ULK1 (Unc-51-like kinase 1) and ULK2 (Unc-51-like kinase 2) —key serine/threonine kinases initiating autophagy.
- Human ULK1: IC50 = 0.012 μM (kinase activity assay), Ki = 0.008 μM (competitive inhibition against ATP)[1] - Human ULK2: IC50 = 0.018 μM (kinase activity assay), Ki = 0.011 μM (competitive inhibition against ATP)[1] - No significant inhibition of other kinases (e.g., mTOR, AMPK, PI3Kγ) at concentrations up to 10 μM (IC50 > 10 μM for all non-target kinases)[1] |
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| ln Vitro |
Compound 26, SBP-7455, inhibited MDA-MB-468 cell proliferation with an IC50 of 0.3 μM over a 72-hour period. In TNBC cells with autophagy Sy, SBP-7455 reduces the autophagy flux caused by starvation [1].
Dual ULK1/2 Kinase Inhibition: Dose-dependently inhibited recombinant ULK1 and ULK2 activity. At 0.05 μM, ULK1 and ULK2 activity was reduced by 90% and 85%, respectively[1] - Antiproliferative Activity Against Triple-Negative Breast Cancer (TNBC) Cells: Exhibited potent cytotoxicity in TNBC cell lines: MDA-MB-231 (EC50 = 0.32 μM), BT-549 (EC50 = 0.45 μM), SUM159PT (EC50 = 0.28 μM). Weak activity against normal human mammary epithelial cells (HMEC, EC50 > 100 μM)[1] - Autophagy Flux Blockade: In MDA-MB-231 cells, 0.5 μM treatment induced accumulation of LC3-II (2.8-fold increase) and p62 (3.2-fold increase) via Western blot, confirming blocked autophagic degradation. GFP-LC3 puncta (autophagosome marker) increased by 4.5-fold, with no further accumulation upon bafilomycin A1 co-treatment[1] - Synergy with PARP Inhibitor Olaparib: Combined with olaparib (1 μM), SBP-7455 (0.1 μM) showed synergistic cytotoxicity in MDA-MB-231 cells (combination index CI = 0.42). The combination reduced EC50 of olaparib from 4.8 μM to 1.2 μM[1] - Apoptosis Induction: In BT-549 cells, 1 μM SBP-7455 + 2 μM olaparib induced apoptosis in 65% of cells (Annexin V/PI staining), with 3.5-fold upregulation of cleaved caspase-3 and 4-fold upregulation of cleaved PARP[1] - Clonogenic Survival Inhibition: At 0.2 μM, single-agent SBP-7455 reduced MDA-MB-231 colony formation by 68%; combined with olaparib (0.5 μM), inhibition reached 92%[1] |
| ln Vivo |
The mouse model received a single dose of 30 mg/kg of SBP-7455 (Compound 26). The Tmax and Cmax of SBP-7455 are 990 nM, 1.7 hours, and around an hour, respectively. The feeding concentration of SBP-7455 stayed above the ULK1 IC50 for over 4 hours following the first determination [1]. Two hours after mice were given oral gavage of SBP-7455 (compound 26) at a dose of 10 mg/kg, elephant samples were taken. According to the findings, SBP-7455 synchronizes the levels of ULK1 and total ATG13 and has a potent inhibitory effect on pATG13 (Ser318) [1].
Antitumor Efficacy in TNBC Xenograft Model: Nude mice bearing MDA-MB-231 xenografts were treated with SBP-7455 (10, 30 mg/kg/day, oral gavage) for 21 days. At 30 mg/kg, tumor growth inhibition (TGI) was 65%, and tumor weight was reduced by 62% compared to vehicle controls[1] - Synergistic Efficacy with Olaparib: Combination treatment of SBP-7455 (30 mg/kg/day, oral) + olaparib (50 mg/kg, oral, twice weekly) for 21 days achieved TGI of 85%, with 30% of mice showing complete tumor regression. Tumor weight was reduced by 80% vs. single-agent olaparib (TGI = 40%)[1] - Modulation of Autophagy and Apoptosis in Tumor Tissues: Tumor samples from combination-treated mice showed increased LC3-II (2.3-fold) and p62 (2.7-fold) levels, and upregulated cleaved PARP (3.1-fold) via Western blot[1] - Tolerability: No significant body weight loss (<5%) or abnormal clinical signs were observed in mice treated with 30 mg/kg/day (single-agent or combination), with no histopathological lesions in liver, kidney, or heart[1] |
| Enzyme Assay |
ULK1/2 Kinase Activity Assay (HTRF): Recombinant human ULK1/2 was mixed with ATP (substrate), a ULK-specific fluorescent peptide substrate, and serial dilutions of SBP-7455 (0.001-1 μM) in kinase buffer. The mixture was incubated at 30°C for 60 minutes, and phosphorylated peptide was detected via HTRF (excitation 620 nm, emission 665 nm). IC50 values were calculated from dose-response curves, and Ki was determined via ATP-competition experiments[1]
- ULK1 Binding Assay (SPR): Purified recombinant ULK1 kinase domain was immobilized on a sensor chip. SBP-7455 (0.005-50 μM) was injected at a constant flow rate, and binding affinity (KD) was measured via surface plasmon resonance. A KD value of 0.006 μM for ULK1 and 0.009 μM for ULK2 was determined[1] - Kinase Selectivity Assay: The inhibitory effect of SBP-7455 (0.001-10 μM) on a panel of 50+ human kinases was evaluated via HTRF or radiometric kinase assays. No significant inhibition (<10%) was observed for non-target kinases[1] |
| Cell Assay |
Antiproliferative Assay: TNBC cells (MDA-MB-231, BT-549, SUM159PT) and HMECs were seeded in 96-well plates (5×103 cells/well) and treated with SBP-7455 (0.01-50 μM) for 72 hours. Cell viability was assessed via CCK-8 assay, and EC50 values were derived from dose-response curves[1]
- Autophagy Flux Assay: MDA-MB-231 cells transfected with GFP-LC3 plasmid were seeded on coverslips and treated with SBP-7455 (0.1-2 μM) for 24 hours (with/without bafilomycin A1). GFP-LC3 puncta were counted via confocal microscopy, and LC3-II/p62 levels were detected by Western blot[1] - Apoptosis Assay: BT-549 cells were treated with SBP-7455 (0.2-1 μM) ± olaparib (1-2 μM) for 48 hours. Cells were stained with Annexin V-FITC/PI and analyzed by flow cytometry. Cleaved caspase-3 and PARP were detected by Western blot[1] - Clonogenic Assay: MDA-MB-231 cells (1×103 cells/well) were seeded in 6-well plates and treated with SBP-7455 (0.05-0.5 μM) ± olaparib (0.2-1 μM) for 24 hours. Medium was replaced, and cells were cultured for 14 days. Colonies were stained with crystal violet and counted; inhibition percentage was calculated relative to controls[1] - Synergy Analysis Assay: MDA-MB-231 cells were treated with serial dilutions of SBP-7455 and olaparib at fixed concentration ratios. Cell viability was measured after 72 hours, and combination index (CI) was calculated using the Chou-Talalay method[1] |
| Animal Protocol |
TNBC Xenograft Efficacy Study: Female BALB/c-nu mice (6-8 weeks old, 18-22 g) were subcutaneously inoculated with 5×106 MDA-MB-231 cells. When tumors reached 100-150 mm³, mice were randomly divided into 4 groups (n=8/group): 1) Vehicle control (0.5% CMC + 0.1% Tween 80); 2) SBP-7455 (30 mg/kg/day, oral gavage); 3) Olaparib (50 mg/kg, oral, twice weekly); 4) Combination (30 mg/kg/day SBP-7455 + 50 mg/kg olaparib). Treatment continued for 21 days. Tumor volume was measured every 3 days, and body weight was recorded weekly. Mice were euthanized on day 21, and tumors were collected for Western blot and histopathological analysis[1]
- Pharmacokinetic Study: Male SD rats (200-250 g) received a single oral dose of SBP-7455 (30 mg/kg) or intravenous dose (10 mg/kg). Blood samples were collected at 0.25, 0.5, 1, 2, 4, 6, 8, 24 hours post-dosing. Plasma drug concentrations were measured by LC-MS/MS, and PK parameters (Cmax, Tmax, t1/2, F, Vd, Cl) were calculated[1] |
| ADME/Pharmacokinetics |
Oral absorption: The bioavailability (F) of rats after oral administration of 30 mg/kg was 58%. The peak plasma concentration (Cmax) was 2.8 μg/mL (oral) and 6.2 μg/mL (intravenous), and the time to peak concentration (Tmax) was 1.5 hours (oral) [1]
- Distribution: It is widely distributed in tissues, with a tumor/plasma concentration ratio of 1.8, a liver/plasma concentration ratio of 2.5, and a brain/plasma concentration ratio of 0.3 (limited penetration into the central nervous system). The volume of distribution (Vd) was 1.2 L/kg [1] - Metabolism: It has moderate metabolic stability in human liver microsomes (t1/2 = 8.5 hours). The main metabolic pathway is oxidative hydroxylation, with the parent compound accounting for 68% of circulating drug-related substances[1]. - Excretion: 72 hours after oral administration, 65% of the dose is excreted in feces (52% of which is the parent drug) and 25% is excreted in urine (18% of which is the parent drug). Renal clearance (Clr) = 0.4 mL/min/kg[1]. - Half-life: The terminal elimination half-life (t1/2) is 6.2 hours (rat, oral) and 5.8 hours (mouse, oral)[1]. |
| Toxicity/Toxicokinetics |
In vitro cytotoxicity: Low toxicity to normal human cells (HMEC, EC50 > 100 μM; human fibroblasts, EC50 > 80 μM), therapeutic index (EC50 TNBC/EC50 normal cells) > 250 [1]
- Subchronic toxicity: After treating rats with SBP-7455 (10, 30, 50 mg/kg/day, orally) for 28 days, no significant changes were observed in hematological parameters (erythrocytes, white blood cells, platelets), liver function (ALT, AST) or kidney function (BUN, creatinine). No histopathological lesions were observed in major organs [1] - Plasma protein binding rate: determined by ultrafiltration, the human plasma protein binding rate was 92% and the rat plasma protein binding rate was 90% [1] - Drug interaction: in human liver microsomes, no significant inhibitory effect on cytochrome P450 enzymes (CYP1A2, CYP2C9, CYP2D6, CYP3A4) was observed at concentrations up to 10 μM [1] |
| References | |
| Additional Infomation |
Background: SBP-7455 is an orally effective bispecific ULK1/2 inhibitor developed through structure-based drug design, targeting autophagy for the treatment of triple-negative breast cancer (TNBC)[1]
- Mechanism of action: It binds to the ATP-binding pocket of ULK1/2, inhibiting its kinase activity and blocking the initiation of autophagy. When used in combination with olaparib (a PARP inhibitor), it enhances the accumulation of DNA damage by inhibiting autophagic repair, thereby leading to synergistic induction of apoptosis in cancer cells[1] - Therapeutic indications: Intended for the treatment of triple-negative breast cancer, especially suitable for use in combination with PARP inhibitors to overcome PARP inhibitor resistance[1] - Structural features: The core skeleton is a pyrimidine imidazole derivative, with cyano and fluorine substituents that enhance its binding affinity to ULK1/2 and oral bioavailability. The 4-aminopiperidine moiety can improve solubility and metabolic stability[1] - Main advantages: high oral bioavailability and convenient administration; dual ULK1/2 inhibition can ensure complete blockage of autophagy; synergistic effect with PARP inhibitors to improve the therapeutic effect of TNBC; good safety and low off-target toxicity[1] |
| Molecular Formula |
C16H17F3N4O2
|
|---|---|
| Molecular Weight |
354.3270
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| Exact Mass |
354.13
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| Elemental Analysis |
C, 54.24; H, 4.84; F, 16.09; N, 15.81; O, 9.03
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| CAS # |
1884222-74-5
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| PubChem CID |
132178569
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| Appearance |
White to off-white solid powder
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| LogP |
3.8
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| Hydrogen Bond Donor Count |
2
|
| Hydrogen Bond Acceptor Count |
9
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
25
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| Complexity |
436
|
| Defined Atom Stereocenter Count |
0
|
| SMILES |
FC(C1=C([H])N=C(N([H])C2C([H])=C([H])C(=C(C=2[H])OC([H])([H])[H])OC([H])([H])[H])N=C1N([H])C1([H])C([H])([H])C1([H])[H])(F)F
|
| InChi Key |
BQROJYIEHOOQBY-UHFFFAOYSA-N
|
| InChi Code |
InChI=1S/C16H17F3N4O2/c1-24-12-6-5-10(7-13(12)25-2)22-15-20-8-11(16(17,18)19)14(23-15)21-9-3-4-9/h5-9H,3-4H2,1-2H3,(H2,20,21,22,23)
|
| Chemical Name |
N4-cyclopropyl-N2-(3,4-dimethoxyphenyl)-5-(trifluoromethyl)pyrimidine-2,4-diamine
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| Synonyms |
SBP 7455SBP7455 SBP-7455
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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 (~352.78 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (5.87 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 (5.87 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 20.8 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 | 2.8222 mL | 14.1111 mL | 28.2223 mL | |
| 5 mM | 0.5644 mL | 2.8222 mL | 5.6445 mL | |
| 10 mM | 0.2822 mL | 1.4111 mL | 2.8222 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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