Potent Anti-Myeloma Activity Of The Novel Bromodomain Inhibitors I-BET151 and I-BET762
| Autor: | Aristeidis Chaidos, Valentina Caputo, Ilaria Marigo, Binbin Liu, Suhail Chaudhry, Katerina Goudevenou, Antonia Rotolo, David F Tough, Nicholas N Smithers, Anna K Bassil, Trevor D Chapman, Nicola R Harker, Olena Barbash, Peter Tummino, Niam Al-Mahdi, Andrea C Haynes, Leanne Cutler, BaoChau Le, Amin Rahemtulla, Irene Roberts, Maurits Kleijnen, Jason Witherington, Nigel J Parr, Rab K Prinjha, Anastasios Karadimitris |
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| Rok vydání: | 2013 |
| Předmět: | |
| Zdroj: | Blood. 122:878-878 |
| ISSN: | 1528-0020 0006-4971 |
| Popis: | Despite the therapeutic advances that followed the introduction of new immunomodulatory drugs and proteasome inhibitors, multiple myeloma (MM) remains an incurable malignancy and eventually all patients develop and succumb to chemo-refractory disease. The recently developed bromodomain and extra terminal (BET) protein inhibitors are novel agents targeting the acetyl-binding pockets of the BET family proteins BRD2-4 and BRDT. BET proteins activate transcription through their ability to bind to acetyl-modified lysine residues of histone tails, thereby serving as chromatin scaffolds that recruit the P-TEFb and PAFc1 complexes to Polymerase II (RNA Pol II), ensuring transcriptional initiation and elongation. In preclinical models, two classes of BET inhibitors, benzodiazepines (e.g JQ1) and quinolones (e.g. I-BET151), have been shown to have significant anti-proliferative activity against a variety of hematologic tumours. However translation of these data to molecules suitable for clinical development has yet to be disclosed. Herein, we tested the anti-myeloma activity and extended the mechanistic insights on two BET inhibitors: the chemical probe molecule I-BET151 and I-BET762, an orally active benzodiazepine suitable for clinical development. I-BET151 was tested in vitro in 6 myeloma cell lines (MMCL) with cytogenetic profiles representative of the most common translocations found in MM. I-BET151 induces apoptosis and cell cycle arrest in all MMCL in a time-dependent manner, with IC50 ranging from 133nM to 411nM at 72hrs. With the exception of KMS11 cells, IC50 was similar in stroma-free conditions and in co-culture with MS5 stromal cells. Similarly, I-BET151 induces apoptosis and cell cycle arrest in primary MM cells (n=4) cultured in the presence of IL-6 and stroma. In a subcutaneous MM mouse model, as compared to placebo, treatment with I-BET151 30mg/Kg/day i.p for 21 days resulted in 4-5 fold reduction in tumour size (p In conclusion, I-BET151 and I-BET762 show potent anti-myeloma activity in vitro and in vivo. I-BET151 inhibition of BRD2-4 binding mediates MYC transcriptional silencing and cell cycle arrest, but MYC-independent mechanism are also likely to mediate the I-BET biological effects in MM. Our data is the first example of an orally active BET inhibitor significantly delaying MM progression in vivo and provides strong rationale for clinical testing in phase I/II trials. Disclosures: Tough: GlaxoSmithKline: Employment. Smithers:GlaxoSmithKline: Employment. Bassil:GlaxoSmithKline: Employment. Chapman:GlaxoSmithKline: Employment. Harker:GlaxoSmithKline: Employment. Barbash:GlaxoSmithKline: Employment. Tummino:GlaxoSmithKline: Employment. Al-Mahdi:GlaxoSmithKline: Employment. Haynes:GlaxoSmithKline: Employment. Cutler:GlaxoSmithKline: Employment. Le:GlaxoSmithKline: Employment. Witherington:GlaxoSmithKline: Employment. Parr:GlaxoSmithKline: Employment. Prinjha:GlaxoSmithKline: Employment. |
| Databáze: | OpenAIRE |
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