Inobrodib | CAS#2222941-37-7 | p300/CBP bromodomain inhibitor

MedKoo Cat#: 207116 | Name: Inobrodib

Description:

WARNING: This product is for research use only, not for human or veterinary use.

Inobrodib, also known as CCS1477, is a potent and selective p300/CBP bromodomain inhibitor, is targeted & differentiated from BET inhibitors in prostate cancer cell lines in vitro. Combination of Inobrodib & JQ1 resulted in a highly synergistic inhibitory effect on proliferation in normal 22Rv1 cells. Global gene expression analysis revealed significantly fewer altered genes after Inobrodib (27 up, 119 down) compared to JQ1 (196 up, 655 down).

Chemical Structure

Inobrodib

CAS#2222941-37-7

Theoretical Analysis

MedKoo Cat#: 207116

Name: Inobrodib

CAS#: 2222941-37-7

Chemical Formula: C30H32F2N4O3

Exact Mass: 534.2442

Molecular Weight: 534.61

Elemental Analysis: C, 67.40; H, 6.03; F, 7.11; N, 10.48; O, 8.98

Price and Availability

Size	Price	Availability
25mg	USD 550.00	2 Weeks
50mg	USD 950.00	2 Weeks
100mg	USD 1,650.00	2 Weeks
200mg	USD 2,950.00	2 Weeks

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Related CAS #

2222941-37-7

Synonym

Inobrodib; Inobrodibum; CCS-1477; CCS 1477; CCS1477;

IUPAC/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

InChi Key

SKDNDJWEBPQKCS-CLHVYKLBSA-N

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

SMILES Code

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

Appearance

Solid powder

Purity

>98% (or refer to the Certificate of Analysis)

Shipping Condition

Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition

Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility

Soluble in DMSO

Shelf Life

>3 years if stored properly

Drug Formulation

This drug may be formulated in DMSO

Stock Solution Storage

0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code

2934.99.9001

More Info

Inobrodib is a potent and selective p300/CBP bromodomain inhibitor, currently in a Ph1 trial for patients with metastatic castration resistant prostate cancer (mCRPC). Inobrodib works by inhibiting the expression and function of the androgen receptor (AR), as well as inhibiting c-Myc. Bromodomain and extraterminal domain (BET) protein inhibitors are also being developed in mCRPC. We have established a BET inhibitor (BETi) resistant 22Rv1 prostate cancer cell line and used this, alongside parental 22Rv1 cells, to characterise the differential effects of p300/CBP vs BET bromodomain inhibition

Product Data

Product Data

Instruction

View handling instruction

Biological target:

CCS1477（CBP-IN-1, CBP/p300-IN-4）is a potent and selective inhibitor of p300/CBP bromodomain. CCS1477 works by inhibiting the expression and function of the androgen receptor (AR), as well as inhibiting c-Myc.

In vitro activity:

Next, the 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, Fig. 3D). Importantly, principal component analyses (PCA) suggested a high level of concordance between biological replicates as shown in sample clustering within treatment groups (Supplementary Fig. S4B). 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; refs. 46, 47). Few pathways displayed enrichment after CCS1477 treatment, with those identified relating mainly to cell-cycle– and DNA-repair–related pathways (Fig. 3E); 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 (Fig. 3E). Reference: Cancer Discov. 2021 May;11(5):1118-1137. http://cancerdiscovery.aacrjournals.org/lookup/pmidlookup?view=long&pmid=33431496

In vivo activity:

Having demonstrated that CCS1477 inhibits AR and C-MYC signaling and prostate cancer cell growth, CCS1477 was examined to see if it inhibited the growth of 22Rv1 mouse xenografts. In a mouse pharmacokinetic study, the time course of CCS1477 and exposure relationship to in vitro cell proliferation and binding characteristics was evaluated (Supplementary Fig. S6A). A single oral dose of 30 mg/kg resulted in free blood concentrations (corrected for protein binding) that were in excess of the 22Rv1 cell line proliferation IC50 (96 nmol/L) and the p300 in-cell binding IC50 (19 nmol/L, NanoBRET) for 10 hours. At no time did the free blood concentrations approach the in-cell binding IC50 for BRD4 (1,060 nmol/L). In 22Rv1 mouse xenografts, oral dosing with CCS1477 significantly (P ≤ 0.001) affected tumor growth at 10 mg/kg daily (QD), 20 mg/kg QD, and 30 mg/kg every other day (QOD; Fig. 5A). All doses tested were well tolerated with no change in body weight or condition of the animals (data not shown). Interestingly, despite treatment being stopped after 28 days, tumor growth inhibition was sustained until day 52, when the study was terminated (Fig. 5A); there were no detectable levels of CCS1477 in plasma or tumor at this time (data not shown). The effects of CCS1477 on AR-FL, AR-V7, and C-MYC protein expression, and AR-regulated genes (KLK3 and TMPRSS2) were examined in tumors collected at days 7, 28, and 52 (Fig. 5B, C and E; Supplementary Fig. S6B and S6C). After 7 days of treatment, CCS1477 had reduced AR-FL, AR-V7, and C-MYC protein expression, at all doses tested (Fig. 5C). In addition, TMPRSS2 but not KLK3 gene expression was reduced (Fig. 5B). At the end of the treatment period at day 28, AR-FL and AR-V7 protein expression was reduced in all dosing groups, as was C-MYC at the 30 mg/kg QOD dosing group (Fig. 5C). In addition, TMPRSS2 gene expression continued to be suppressed by CCS1477 at day 28, and at this time point the 20 mg/kg QD and the 30 mg/kg QOD doses decreased KLK3 gene expression (Fig. 5B). At day 52, after 24 days without CCS1477 treatment, all protein biomarkers had returned to control levels but there was prolonged reduction in KLK3 and TMPRSS2 gene expression, particularly at the 30 mg/kg QOD dose (Supplementary Fig. S6B and S6C). In addition to tumor pharmacodynamic analyses, plasma KLK3 levels increased in the vehicle group between days 0 and 28, reflecting the increase in tumor volume during this time (Fig. 5D). Treatment with CCS1477 at all doses caused a decrease in the plasma KLK3 concentrations (Fig. 5D). Finally, RNA-sequencing analysis of tumors treated with 20 mg/kg QD for 28 days demonstrated de-enrichment of signatures of AR and AR-V7 signaling when compared with vehicle, with the AR response pathway identified as one of the top de-enriched pathways (Fig. 5E; Supplementary Table S7). Although there was a trend toward de-enrichment of MYC targets, in contrast to the 22Rv1 cell line experiments, this was not significant (Fig. 5E). Taken together, these data demonstrate that inhibition of CBP and p300 by CCS1477 suppresses growth of a 22Rv1 mouse xenograft model with associated reduction in AR signaling. Reference: Cancer Discov. 2021 May;11(5):1118-1137. http://cancerdiscovery.aacrjournals.org/lookup/pmidlookup?view=long&pmid=33431496

	Solvent	mg/mL	mM
Solubility
	Ethanol	100.0	187.06

Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.

Preparing Stock Solutions

The following data is based on the product molecular weight 534.61 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Concentration / Solvent Volume / Mass	1 mg	5 mg	10 mg
1 mM	1.15 mL	5.76 mL	11.51 mL
5 mM	0.23 mL	1.15 mL	2.3 mL
10 mM	0.12 mL	0.58 mL	1.15 mL
50 mM	0.02 mL	0.12 mL	0.23 mL

Formulation protocol:

In vitro protocol:

1. Welti J, Sharp A, Brooks N, Yuan W, McNair C, Chand SN, Pal A, Figueiredo I, Riisnaes R, Gurel B, Rekowski J, Bogdan D, West W, Young B, Raja M, Prosser A, Lane J, Thomson S, Worthington J, Onions S, Shannon J, Paoletta S, Brown R, Smyth D, Harbottle GW, Gil VS, Miranda S, Crespo M, Ferreira A, Pereira R, Tunariu N, Carreira S, Neeb AJ, Ning J, Swain A, Taddei D; SU2C/PCF International Prostate Cancer Dream Team, Schiewer MJ, Knudsen KE, Pegg N, de Bono JS. Targeting the p300/CBP Axis in Lethal Prostate Cancer. Cancer Discov. 2021 May;11(5):1118-1137. doi: 10.1158/2159-8290.CD-20-0751. Epub 2021 Jan 11. PMID: 33431496; PMCID: PMC8102310.

In vivo protocol:

1: Rasool RU, Natesan R, Asangani IA. Toppling the HAT to Treat Lethal Prostate Cancer. Cancer Discov. 2021 May;11(5):1011-1013. doi: 10.1158/2159-8290.CD-21-0184. PMID: 33947717. 2: Welti J, Sharp A, Brooks N, Yuan W, McNair C, Chand SN, Pal A, Figueiredo I, Riisnaes R, Gurel B, Rekowski J, Bogdan D, West W, Young B, Raja M, Prosser A, Lane J, Thomson S, Worthington J, Onions S, Shannon J, Paoletta S, Brown R, Smyth D, Harbottle GW, Gil VS, Miranda S, Crespo M, Ferreira A, Pereira R, Tunariu N, Carreira S, Neeb AJ, Ning J, Swain A, Taddei D; SU2C/PCF International Prostate Cancer Dream Team, Schiewer MJ, Knudsen KE, Pegg N, de Bono JS. Targeting the p300/CBP Axis in Lethal Prostate Cancer. Cancer Discov. 2021 May;11(5):1118-1137. doi: 10.1158/2159-8290.CD-20-0751. Epub 2021 Jan 11. PMID: 33431496; PMCID: PMC8102310. 3: He ZX, Wei BF, Zhang X, Gong YP, Ma LY, Zhao W. Current development of CBP/p300 inhibitors in the last decade. Eur J Med Chem. 2021 Jan 1;209:112861. doi: 10.1016/j.ejmech.2020.112861. Epub 2020 Oct 1. PMID: 33045661.

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