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Inobrodib (CCS1477; BP-IN-1; CCS-1477) is a novel, potent and selective p300/CBP bromodomain inhibitor with anticancer activity. The combination of CCS-1477 and JQ1 resulted in a highly synergistic inhibitory effect on proliferation in normal 22Rv1 cells. Inobrodib (CCS1477) inhibits p300 and CBP with Kd values of 1.3 and 1.7 nM, respectively, and with 170/130-fold selectivity compared with BRD4 with a Kd of 222 nM. CCS1477, a selective inhibitor of p300/CBP bromodomain, disrupts AR- and MYC-regulated gene expression, suppresses tumor growth in vivo in multiple castration-resistant prostate cancer xenograft models, and modulates biomarker expression in early clinical evaluation, providing a novel therapeutic approach for AR-addicted advanced prostate cancer. CCS1477 is currently being evaluated in a phase I trial for the treatment of hematologic malignancies and advanced prostate cancer and is the first of its class to enter a clinical trial stage.
| Targets |
p300/CBP bromodomain (Kd for p300 = 1.3 nM; Kd for CBP = 1.7 nM)
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| ln Vitro |
In intracellular BRET tests, inobrodib binds to cellular histones with IC50 values of 19 nM for p300 and 1060 nM for BRD4. When applied to 22Rv1 and LNCaP95 cells expressing AR-FL and AR-V7 (IC50 all < 100), inobrodib (0-3000 nM; 48 hours) decreases the expression of AR-regulated genes (KLK2, KLK3, and TMPRSS2). Inobrodib exhibits strong growth inhibitory action in nM) and decreases the expression of LNCaP95 and 22Rv1 cells [1]. Has no discernible impact on the expression of AR-FL protein in 22Rv1 and LNCaP95 cells, but did have an impact on the expression of C-MYC and AR-V7 proteins in 22Rv1 cells. Inobrodib C-Inobrodib in 16 hours and 22Rv1 and C4-2 cells Inobrodib has the ability to completely eradicate the persistent AR presence in CRPC signaling by influencing the recruitment of CBP, p300, and AR-FL to recognized AR binding sites. [1].
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| ln Vivo |
The growth and topology of the 22Rv1 mouse xenograft model are inhibited by inobrodib (10–30 mg/kg; oral gavage; 10 or 20 mg/kg daily (QD) or 30 mg/kg every other day (QOD) for 28 days). Inobrodib (20 mg/kg; oral gavage; daily for 8 days) decreases AR and AR-V7 signaling and inhibits tumor growth in a patient-derived lethal tumor model [1].
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| Cell Assay |
CRPC cell line 22Rv1 was selected to investigate the impact of CCS1477 treatment on its transcriptome through RNA sequencing (at derived IC50; 96 nmol/L). Importantly, principal component analyses (PCA) suggested a high level of concordance between biological replicates as shown in sample clustering within treatment groups. Significant transcriptional alterations were identified after drug treatment, with 3,406 transcripts induced and 3,262 repressed (Supplementary Fig. S4C). To investigate pathways associated with the gene-expression changes seen, gene set enrichment analysis (GSEA) was performed using the Hallmarks gene set from the Molecular Signatures Database (MSigDB). Few pathways displayed enrichment after CCS1477 treatment, with those identified relating mainly to cell-cycle– and DNA-repair–related pathways; critically, those with attenuated enrichment after CCS1477 treatment included androgen response and MYC target pathways, validating p300/CBP knockdown data and further implicating these in modulating these key prostate cancer signaling pathways [1].
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| Animal Protocol |
Animal/Disease Models: non-castrated male athymic nude mice [1]
Doses: 10-30 mg/kg Route of Administration: po (oral gavage); 10 or 20 mg/kg daily (QD) or 30 mg/kg every other day (QOD ) for 28 days Experimental Results: Effect on tumor growth at 10 mg/kg per day, 20 mg/kg per day, and 30 mg/kg per time on another day. |
| References |
[1]. Rasool RU, et al. Toppling the HAT to Treat Lethal Prostate Cancer. Cancer Discov. 2021;11(5):1011-1013.
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| Molecular Formula |
C₃₀H₃₂F₂N₄O₃
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|---|---|
| Molecular Weight |
534.60
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| Exact Mass |
534.24
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| Elemental Analysis |
C, 67.40; H, 6.03; F, 7.11; N, 10.48; O, 8.98
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| CAS # |
2222941-37-7
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| Related CAS # |
2222941-37-7
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| Appearance |
White to off-white solid
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| LogP |
4.9
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| tPSA |
73.4Ų
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| SMILES |
O=C1N(C2=CC=C(F)C(F)=C2)[C@H](C3=NC4=CC(C5=C(C)ON=C5C)=CC=C4N3[C@H]6CC[C@H](OC)CC6)CCC1
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| InChi Key |
SKDNDJWEBPQKCS-CLHVYKLBSA-N
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| InChi Code |
InChI=1S/C30H32F2N4O3/c1-17-29(18(2)39-34-17)19-7-14-26-25(15-19)33-30(36(26)20-8-11-22(38-3)12-9-20)27-5-4-6-28(37)35(27)21-10-13-23(31)24(32)16-21/h7,10,13-16,20,22,27H,4-6,8-9,11-12H2,1-3H3/t20-,22-,27-/m0/s1
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| Chemical Name |
(S)-1-(3,4-difluorophenyl)-6-(5-(3,5-dimethylisoxazol-4-yl)-1-((1r,4S)-4-methoxycyclohexyl)-1H-benzo[d]imidazol-2-yl)piperidin-2-one
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| Synonyms |
CBP-IN-1CBP IN-1Inobrodib CBP-IN 1CCS-1477 CCS 1477 CCS1477
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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 : ~100 mg/mL (~187.06 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 5.25 mg/mL (9.82 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 52.5 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: ≥ 5.25 mg/mL (9.82 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 52.5 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (4.68 mM) in 5% DMSO + 40% PEG300 + 5% Tween80 + 50% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: ≥ 2.5 mg/mL (4.68 mM) (saturation unknown) in 5% DMSO + 95% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. 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. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.8706 mL | 9.3528 mL | 18.7056 mL | |
| 5 mM | 0.3741 mL | 1.8706 mL | 3.7411 mL | |
| 10 mM | 0.1871 mL | 0.9353 mL | 1.8706 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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