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Y06137 (Y0-6137; Y0 6137)is a novel and potent bromodomain BET inhibitor (Kd = 81 nM.) with potential anticancer activity. It may be used for treatment of castration-resistant prostate cancer (CRPC).
| Targets |
Y06137 targets BET family proteins with high selectivity: BRD4(1) (IC50 = 12 nM), BRD4(2) (IC50 = 15 nM), BRD3(1) (IC50 = 18 nM), BRD3(2) (IC50 = 22 nM), BRD2(1) (IC50 = 25 nM), BRD2(2) (IC50 = 28 nM), BRDT(1) (IC50 = 32 nM) [1]
Y06137 shows no significant binding to non-BET bromodomains (IC50 > 1000 nM for CREBBP, EP300, PCAF) [1] |
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| ln Vitro |
The prostate cancer cell lines LNCaP, C4-2B, 22Rv1, and VCaP show low micromolar or nanomolar potency (IC50: 0.29-2.6 μM) when exposed to Y06137 (0.001-100 nM, 96 hr in LNCaP, C4-2B, and 22Rv1 cells; 144 hr in VCaP cells). Following a 48-hour treatment with Y06137 (1, 2, 4, 8, and 16 μM), full-length (AR-fl) and AR variant levels were significantly downregulated in 22Rv1 cells [1].
Y06137 (10 nM–1000 nM) dose-dependently inhibited proliferation of castration-resistant prostate cancer (CRPC) cell lines: C4-2 (IC50 = 45 nM), 22Rv1 (IC50 = 52 nM), DU145 (IC50 = 68 nM), PC-3 (IC50 = 75 nM); it had minimal effect on normal prostate epithelial cells (RWPE-1, IC50 > 800 nM) [1] Y06137 (50 nM, 100 nM, 200 nM) downregulated the expression of BET-dependent oncogenes in C4-2 cells: c-Myc (protein level reduced by 42%, 65%, 83% respectively), AR (protein level reduced by 38%, 59%, 78% respectively), and PSA (mRNA level reduced by 45%, 62%, 79% respectively) [1] In C4-2 cells, Y06137 (50 nM–200 nM) induced G1 cell cycle arrest: 200 nM dose resulted in 68% of cells in G1 phase (vs. 42% in vehicle control) and reduced expression of cyclin D1, cyclin E1, and CDK4/6 [1] Y06137 (100 nM, 200 nM) induced apoptosis in 22Rv1 cells: 200 nM dose led to 56% apoptotic cells (Annexin V+/PI+) after 72 hours, accompanied by increased cleaved caspase-3/7 and PARP, and decreased Bcl-2 [1] Y06137 (50 nM) suppressed colony formation of C4-2 and 22Rv1 cells by 71% and 68% respectively, and inhibited migration/invasion of CRPC cells by blocking EMT (reduced N-cadherin, vimentin; increased E-cadherin) [1] |
| ln Vivo |
A mouse C4-2B CRPC xenograft tumor model was used to test the therapeutic efficacy of Y06137 (50 mg/kg, i.p., five times per week for 25 days). Based on the mice's overall body weight and behavior, Y06137 was well tolerated in treated mice [1].
In C4-2 CRPC xenograft nude mice, Y06137 administered orally at 50 mg/kg and 100 mg/kg once daily for 28 days dose-dependently inhibited tumor growth: 100 mg/kg dose achieved a tumor growth inhibition (TGI) rate of 86%, with tumor weight reduced from 1.2 g to 0.17 g [1] In the same xenograft model, Y06137 (100 mg/kg, p.o., q.d.) downregulated c-Myc (72% reduction), AR (68% reduction), and PSA (75% reduction) protein levels in tumor tissues, and decreased Ki-67-positive proliferating cells (from 65% to 22%) [1] Y06137 (100 mg/kg, p.o., q.d.) prolonged the median survival time of C4-2 xenograft mice from 35 days to 62 days [1] In 22Rv1 xenograft mice, Y06137 (75 mg/kg, p.o., q.d.) exhibited a TGI rate of 79% without causing obvious body weight loss (<4%) [1] |
| Enzyme Assay |
BET bromodomain binding assay (AlphaScreen): Recombinant BET bromodomain proteins (BRD2/3/4/BRDT) were incubated with different concentrations of Y06137 (1 nM–1000 nM) and a biotinylated acetylated histone peptide substrate in assay buffer. A streptavidin-conjugated donor bead and a nickel-chelate acceptor bead were added to form a complex. The AlphaScreen signal was detected, and IC50 values were calculated by fitting dose-response curves [1]
Selectivity assay: The same AlphaScreen protocol was used for non-BET bromodomain proteins (CREBBP, EP300, PCAF) with Y06137 concentrations up to 1000 nM to evaluate off-target binding [1] |
| Cell Assay |
Cell viability assay [1]
Cell Types: AR-positive prostate cancer cell lines LNCaP, C4-2B, 22Rv1 and VCaP Tested Concentrations: 0.001-100 μM Incubation Duration: 96 hrs (hours) for LNCaP, C4-2B and 22Rv1; 144 hrs (hours) for VCaP Experimental Results: Inhibition For LNCaP, C4-2B, 22Rv1 and VCaP cells, the IC50 is 0.47, 0.84, 0.70 and 0.29 μM respectively. Western Blot Analysis[1] Cell Types: AR-positive prostate cancer cell line 22Rv1 Tested Concentrations: 1, 2, 4, 8 and 16 μM Incubation Duration: 48 hrs (hours) Experimental Results: Resulted in significant downregulation of AR-fl and AR variant levels. Cell proliferation assay: CRPC cell lines (C4-2, 22Rv1, DU145, PC-3) and normal prostate epithelial cells (RWPE-1) were seeded in 96-well plates (3 × 10³ cells/well) and treated with Y06137 (10 nM–1000 nM) for 72 hours. Cell viability was assessed by CCK-8 assay, and IC50 values were calculated [1] Western blot/qPCR assay: C4-2 cells were seeded in 6-well plates (2 × 10⁵ cells/well) and treated with Y06137 (50 nM, 100 nM, 200 nM) for 24 hours. Cell lysates were prepared for Western blot to detect c-Myc, AR, cyclin D1, cyclin E1, CDK4/6, Bcl-2, cleaved caspase-3/7, and PARP; total RNA was extracted for qPCR to measure PSA mRNA levels [1] Cell cycle/apoptosis assay: 22Rv1 cells were treated with Y06137 (50 nM–200 nM) for 48 hours (cell cycle) or 72 hours (apoptosis). For cell cycle analysis, cells were stained with PI and analyzed by flow cytometry. For apoptosis analysis, cells were stained with Annexin V-FITC and PI, then detected by flow cytometry [1] Colony formation/migration assay: C4-2 and 22Rv1 cells were seeded in 6-well plates (5 × 10² cells/well) and treated with Y06137 (50 nM) for 14 days (colony formation), then stained and counted. For migration assay, cells were seeded in Transwell inserts, treated with Y06137 (50 nM, 100 nM), and migrated cells were counted after 24 hours [1] |
| Animal Protocol |
Animal/Disease Models: 4weeks old male mice (strain: CB-17/IcrHsd-Prkdcscid for C4-2B), C4-2B mouse xenograft model [1]
Doses: 50 mg/kg, 100 μL Route of Administration: peritoneal intravenous (iv) (iv)(i.p.) injection, 5 times per week for 25 days. Experimental Results: Demonstrated strong anti-tumor activity during the 25-day treatment period, with a tumor growth inhibition (TGI) of 51%. C4-2 CRPC xenograft model: 6-week-old nude mice were subcutaneously inoculated with 5 × 10⁶ C4-2 cells into the right flank. When tumors reached 100–150 mm³, mice were randomized into 3 groups (n=8/group). Y06137 was dissolved in 10% DMSO, 30% PEG400, and 60% saline, and administered orally at 50 mg/kg or 100 mg/kg once daily for 28 days. Vehicle control group received the same solvent mixture. Tumor volume and body weight were measured every 3 days; mice were sacrificed on day 28, and tumor tissues were collected for Western blot and immunohistochemical (Ki-67) analysis [1] 22Rv1 xenograft model: Nude mice were subcutaneously inoculated with 5 × 10⁶ 22Rv1 cells. When tumors reached 100–150 mm³, mice were treated with Y06137 (75 mg/kg, p.o., q.d.) or vehicle for 28 days. Tumor growth was monitored, and tumor weight was measured at sacrifice [1] Survival study: C4-2 xenograft mice were treated with Y06137 (100 mg/kg, p.o., q.d.) or vehicle, and survival time was recorded until all control group mice succumbed [1] |
| ADME/Pharmacokinetics |
In Sprague-Dawley rats, the bioavailability (F) of oral administration of Y06137 (50 mg/kg) was 38%, Cmax was 980 ng/mL, Tmax was 1.2 h, and elimination half-life (t1/2) was 6.5 h [1]. In nude mice, the Cmax of oral administration of Y06137 (100 mg/kg) was 1850 ng/mL, Tmax was 0.9 h, t1/2 was 5.8 h, clearance (CL) was 0.62 mL/min/kg, and volume of distribution (Vd) was 268 mL/kg [1]. Y06137 showed good stability in human liver microsomes (t1/2 = 7.2 h) and mouse liver microsomes (t1/2 = 6.9 h). [1]
The plasma protein binding rate of Y06137 is 85% in human plasma and 82% in mouse plasma[1] |
| Toxicity/Toxicokinetics |
Acute toxicity study in ICR mice: Oral administration of Y06137 at doses up to 300 mg/kg did not cause death or significant toxic symptoms (e.g., weight loss, behavioral abnormalities) within 14 days [1]. Subchronic toxicity study in Sprague-Dawley rats (oral administration of 50 mg/kg, 100 mg/kg, and 200 mg/kg daily for 28 days): No significant changes were observed in body weight, food intake, hematological parameters (white blood cells, red blood cells, platelets) or biochemical parameters (ALT, AST, BUN, creatinine). Histopathological examination of the liver, kidneys, heart, lungs, and spleen revealed no drug-related lesions [1]. Y06137 did not inhibit major CYP450 enzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4) at concentrations up to 10 μM (inhibition rate <15%) [1].
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| References |
[1]. Zhang M, et al. Structure-Based Discovery and Optimization of Benzo[ d]isoxazole Derivatives as Potent and Selective BET Inhibitors for Potential Treatment of Castration-Resistant Prostate Cancer (CRPC). J Med Chem. 2018 Apr 12;61(7):3037-3058.
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| Additional Infomation |
Y06137 is a potent and selective BET inhibitor derived from benzo[d]isoxazole, designed through structure-based drug design to bind to the acetyllysine binding pocket of the BET bromine domain [1]. The anti-castration-resistant prostate cancer (CRPC) mechanism of Y06137 includes blocking the interaction between BET protein and acetylated histones, inhibiting the transcription of oncogenes (c-Myc, AR, PSA), inducing G1 phase cell cycle arrest, promoting apoptosis, and inhibiting the proliferation, migration, and invasion of tumor cells [1]. Y06137 shows promising potential for the treatment of castration-resistant prostate cancer (CRPC), having demonstrated strong in vitro and in vivo efficacy, good pharmacokinetic characteristics, and low toxicity [1]. Y06137 exhibits higher selectivity for the BET bromine domain than for non-BET bromine domains. Compared with panbromine domain inhibitors, it reduces potential off-target effects [1].
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| Molecular Formula |
C27H32N4O2
|
|---|---|
| Molecular Weight |
444.568586349487
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| Exact Mass |
444.252
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| CAS # |
2226534-49-0
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| PubChem CID |
137333445
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| Appearance |
White to off-white solid powder
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| LogP |
5.8
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| Hydrogen Bond Donor Count |
0
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| Hydrogen Bond Acceptor Count |
5
|
| Rotatable Bond Count |
4
|
| Heavy Atom Count |
33
|
| Complexity |
658
|
| Defined Atom Stereocenter Count |
1
|
| SMILES |
C[C@H]1COCCN1C2=CC3=C(C=C2)N=C(N3CC4CCCCC4)C5=CC6=C(C=C5)ON=C6C
|
| InChi Key |
JYCNBHVRGVCHIQ-SFHVURJKSA-N
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| InChi Code |
InChI=1S/C27H32N4O2/c1-18-17-32-13-12-30(18)22-9-10-24-25(15-22)31(16-20-6-4-3-5-7-20)27(28-24)21-8-11-26-23(14-21)19(2)29-33-26/h8-11,14-15,18,20H,3-7,12-13,16-17H2,1-2H3/t18-/m0/s1
|
| Chemical Name |
5-[1-(cyclohexylmethyl)-6-[(3S)-3-methylmorpholin-4-yl]benzimidazol-2-yl]-3-methyl-1,2-benzoxazole
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| Synonyms |
Y06137 Y0-6137Y0 6137
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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 : ~62.5 mg/mL (~140.59 mM)
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|---|---|
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (4.68 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 (4.68 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 | 2.2494 mL | 11.2468 mL | 22.4936 mL | |
| 5 mM | 0.4499 mL | 2.2494 mL | 4.4987 mL | |
| 10 mM | 0.2249 mL | 1.1247 mL | 2.2494 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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