BET inhibitors in cancer therapeutics: a patent review

Ghoshal, Anirban; Yugandhar, Doddapaneni; Srivastava, Ajay Kumar

doi:10.1517/13543776.2016.1159299

Cited by 34 publications

(22 citation statements)

References 33 publications

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“…We focused on two groups of inhibitors: those targeting bromodomains and those targeting CDK9. Both classes of compounds repress proliferation, induce apoptosis, and reduce tumor growth, with many of these now employed in clinical trials [ 27 , 28 ].…”

Section: Discussionmentioning

confidence: 99%

“…BRD4, of note, is known to act as a key player in Sonic-hedgehog signaling that again is a driver of RT tumorigenesis [ 8 , 10 , 16 , 26 ]. Hence, inhibition of BRD4 as well as CDK9 with small molecule inhibitors have been demonstrated to display antitumoral effects in various studies [ 27 , 28 ]. As RT are characterized by altered functionality of the SWI/SNF chromatin remodeling complex, the entity represents a promising option for testing novel inhibitor compounds with an impact on specific molecules involved in epigenetic and transcriptional regulation mechanisms.…”

Section: Introductionmentioning

confidence: 99%

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Combined BRD4 and CDK9 inhibition as a new therapeutic approach in malignant rhabdoid tumors

et al. 2017

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Rhabdoid tumors are caused by the deletion of SMARCB1, whose protein encodes the SMARCB1 subunit of the chromatin remodeling complex SWI/SNF that is involved in global chromatin organization and gene expression control. Simultaneously inhibiting the main players involved in the deregulated transcription machinery is a promising option for preventing exaggerated tumor cell proliferation and survival as it may bypass compensatory mechanisms. In support of this hypothesis, we report efficient impairment of cellular proliferation and strong induction of cell death elicited by inhibition of bromodomain protein BRD4 and transcription kinase CDK9 using small molecular compounds. Combination of both compounds efficiently represses antiapoptotic genes and the oncogene MYC. Our results provide a novel approach for the treatment of RT.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Combined BRD4 and CDK9 inhibition as a new therapeutic approach in malignant rhabdoid tumors

et al. 2017

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“…Inhibition of BET bromodomains is envisioned to help in evading several forms of cancers, by halting the expression of genes important for tumor growth [ 5 ]. Recently, several selective and highly potent pan-BET inhibitors have been extensively pursued by the scientific community, demonstrating their potential anti-tumor activity in cell [ 21 – 25 ]. The five BET family inhibitors, namely RVX-208, I-BET 762, OTX 015, CPI-0610 and TEN-010 were registered for active clinical trials, for investigating the BET proteins against various diseases [ 22 ].…”

Section: Introductionmentioning

confidence: 99%

A Novel Phenanthridionone Based Scaffold As a Potential Inhibitor of the BRD2 Bromodomain: Crystal Structure of the Complex

et al. 2016

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Bromodomain containing proteins recognize the level of histone acetylation and regulate epigenetically controlled processes like gene transcription and chromatin modification. The BET (bromodomain and extra-terminal) family proteins, which are transcriptional co-regulators, have been implicated in the pathogenesis of cancer, neurodegenerative disorders, and defects in embryonic stem cell differentiation. Inhibitors selectively targeting the BET bromodomains can pave the path for new drug discovery against several forms of major diseases. By a rational structure-based approach, we have identified a new inhibitor (NSC127133) of the second bromodomain (BD2) of the BET family protein BRD2 using the NCI Diversity Set III library. A high-resolution crystal structure of the BRD2-BD2 in complex with this compound and in apo- form is refined to 0.91 and 0.94 Å, respectively. The compound, which is a phenanthridinone derivative, binds well to the acetyl-lysine binding pocket of BD2 and displays significant hydrophobic and hydrophilic interactions. Moreover, the atomic resolution data obtained in this study allowed us to visualize certain structural features of BD2 which remained unobserved so far. We propose that the discovered compound may be a potential molecule to develop a new library for inhibiting the BRD2-BD2 function.

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“…The bromodomain containing protein 4 (BRD4) is a key therapeutic target for Bromodomain and extra-terminal domain (BET) inhibitors, a group of pharmaceutical drugs that have recently gone under the clinical trials [ 1 , 2 ]. BRD4 plays a vital role in the expression of “tumor driving” oncogenes, as shown in myeloid leukemia, multiple myeloma, and basal-like breast cancer [ 3 , 4 ].…”

Section: Introductionmentioning

confidence: 99%

Investigations of Structural Requirements for BRD4 Inhibitors through Ligand- and Structure-Based 3D QSAR Approaches

et al. 2018

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The bromodomain containing protein 4 (BRD4) recognizes acetylated histone proteins and plays numerous roles in the progression of a wide range of cancers, due to which it is under intense investigation as a novel anti-cancer drug target. In the present study, we performed three-dimensional quantitative structure activity relationship (3D-QSAR) molecular modeling on a series of 60 inhibitors of BRD4 protein using ligand- and structure-based alignment and different partial charges assignment methods by employing comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) approaches. The developed models were validated using various statistical methods, including non-cross validated correlation coefficient (r2), leave-one-out (LOO) cross validated correlation coefficient (q2), bootstrapping, and Fisher’s randomization test. The highly reliable and predictive CoMFA (q2 = 0.569, r2 = 0.979) and CoMSIA (q2 = 0.500, r2 = 0.982) models were obtained from a structure-based 3D-QSAR approach using Merck molecular force field (MMFF94). The best models demonstrate that electrostatic and steric fields play an important role in the biological activities of these compounds. Hence, based on the contour maps information, new compounds were designed, and their binding modes were elucidated in BRD4 protein’s active site. Further, the activities and physicochemical properties of the designed molecules were also predicted using the best 3D-QSAR models. We believe that predicted models will help us to understand the structural requirements of BRD4 protein inhibitors that belong to quinolinone and quinazolinone classes for the designing of better active compounds.

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BET inhibitors in cancer therapeutics: a patent review

Cited by 34 publications

References 33 publications

Combined BRD4 and CDK9 inhibition as a new therapeutic approach in malignant rhabdoid tumors

Combined BRD4 and CDK9 inhibition as a new therapeutic approach in malignant rhabdoid tumors

A Novel Phenanthridionone Based Scaffold As a Potential Inhibitor of the BRD2 Bromodomain: Crystal Structure of the Complex

Investigations of Structural Requirements for BRD4 Inhibitors through Ligand- and Structure-Based 3D QSAR Approaches

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