Last update 01 Nov 2024

BRD4 x TAF1

Last update 01 Nov 2024

Basic Info

Related Targets

BRD4TAF1

Drugs associated with BRD4 x TAF1

N2817

Target

BRD4 x TAF1

Mechanism

BRD4 inhibitors [+1]

Active Org.

Shanghai Institute of Materia Medica Chinese Academy of Sci

Originator Org.

Shanghai Institute of Materia Medica Chinese Academy of Sci

Active Indication

Neoplasms

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with BRD4 x TAF1

100 Translational Medicine associated with BRD4 x TAF1

0 Patents (Medical) associated with BRD4 x TAF1

Literatures (Medical) associated with BRD4 x TAF1

01 Jun 2024·Current Opinion in Genetics & Development

Therapeutic targeting of BET bromodomain and other epigenetic acetylrecognition domain–containing factors

Review

Author: Shilatifard, Ali ; Gold, Sarah

Development of cancer therapies targeting chromatin modifiers and transcriptional regulatory factors is rapidly expanding to include new targets and novel targeting strategies. At the same time, basic molecular research continues to refine our understanding of the epigenetic mechanisms regulating transcription, gene expression, and oncogenesis. This mini-review focuses on cancer therapies targeting the chromatin-associated factors that recognize histone lysine acetylation. Recently reported safety and efficacy are discussed for inhibitors targeting the bromodomains of bromodomain and extraterminal domain (BET) family proteins. In light of recent results indicating that the transcriptional regulator BRD4-PTEFb can function independently of BRD4's bromodomains, the clinical trial performance of these BET inhibitors is placed in a broader context of existing and potential strategies for targeting BRD4-PTEFb. Recently developed therapies targeting bromodomain-containing factors within the SWI/SNF (BAF) family of chromatin remodeling complexes are discussed, as is the potential for targeting the bromodomain-containing transcription factor TAF1 and the YEATS acetylrecognition domain-containing factor GAS41. Recent findings regarding the selectivity and combinatorial specificity of acetylrecognition are highlighted. In conclusion, the potential for further development is discussed with a focus on proximity-based therapies targeting this class of epigenetic factors.

01 Aug 2023·American journal of medical genetics. Part A

Genomic analyses in Cornelia de Lange Syndrome and related diagnoses: Novel candidate genes, genotype-phenotype correlations and common mechanisms.

Article

Author: Ramos, Feliciano ; Liu, Jinglan ; Ramanathan, Subhadra ; Graham, John M ; Rio, Marlene ; Anyane-Yeboa, Kwame ; Heidenreich, Randy ; Jackson, Marie ; Hoffman, Jodi ; Zackai, Elaine ; Krantz, Ian D ; Izumi, Kosuke ; Rope, Alan F ; Roeder, Elizabeth ; Gripp, Karen W ; Musio, Antonio ; Harrington, Ann Tokay ; Rajagopalan, Ramakrishnan ; Rentas, Stefan ; Tayoun, Ahmad Abou ; Scheuerle, Angela E ; Semeo, Benjamin ; Al Rawi, Zayd ; Schneider, Adele ; Armstrong, Linlea ; Shalev, Stavit ; Fortunato, Sierra ; Wheeler, Patricia G ; Nampoothiri, Sheela ; Argente, Jesús ; Young, Terri ; Conlin, Laura ; Katz, Olivia ; Cox, Gerald F ; Gupta, Neerja ; Arn, Pamela H ; Zhe, Zhang ; Kline, Antonie D ; Meagher, Kirsten ; Stevens, Cathy ; Bird, Lynne M ; Pie, Juan ; Bruegger, Daniel ; Dave, Usha ; Field, Michael ; Loomes, Kathleen M ; White, Susan M ; Do, Wonwook ; Allen, Bill ; Raskin, Salmo ; Xu, Dongbin ; Chitayat, David ; Tkemaladze, Tinatin ; Turner, Anne ; Smith, Rosemarie ; McEldrew, Deborah ; Kaur, Maninder ; DeBaere, Elfrede ; Clark, Dinah ; Mendelsohn, Nancy ; Lawrence, Audrey ; Yamamoto, Nobuko ; Angula, Moris A ; Leroy, Julian ; Wilde, Jonathan J ; Wallace, Nina ; Clark, Robin ; Mehta, Devanshi ; Basel-Salmon, Lina ; McCallum, Jennifer ; Schindler, Emma ; Deardorff, Matthew A ; Toimie, John ; Kim, Jiwoo ; Lace, Baiba ; Powell, Cynthia M ; Sangha, Karan ; Siu, Victoria ; Pipan, Mary ; Moeschler, John ; Toriello, Helga ; Baynam, Gareth ; Raible, Sarah E ; Micule, Ieva ; McDonald, Marie ; Hopkin, Robert J ; Devkota, Batsal ; Kariminejad, Ariana ; Blair, Justin ; Kogan, Jillene ; Jones, Kenneth L ; Greenstein, Robert ; Ohashi, Kaoru ; Ch'ng, Gaik-Siew ; Lynch, Sally Ann ; Jones, Marilyn C ; Abdul-Rahman, Omar

Cornelia de Lange Syndrome (CdLS) is a rare, dominantly inherited multisystem developmental disorder characterized by highly variable manifestations of growth and developmental delays, upper limb involvement, hypertrichosis, cardiac, gastrointestinal, craniofacial, and other systemic features. Pathogenic variants in genes encoding cohesin complex structural subunits and regulatory proteins (NIPBL, SMC1A, SMC3, HDAC8, and RAD21) are the major pathogenic contributors to CdLS. Heterozygous or hemizygous variants in the genes encoding these five proteins have been found to be contributory to CdLS, with variants in NIPBL accounting for the majority (>60%) of cases, and the only gene identified to date that results in the severe or classic form of CdLS when mutated. Pathogenic variants in cohesin genes other than NIPBL tend to result in a less severe phenotype. Causative variants in additional genes, such as ANKRD11, EP300, AFF4, TAF1, and BRD4, can cause a CdLS-like phenotype. The common role that these genes, and others, play as critical regulators of developmental transcriptional control has led to the conditions they cause being referred to as disorders of transcriptional regulation (or "DTRs"). Here, we report the results of a comprehensive molecular analysis in a cohort of 716 probands with typical and atypical CdLS in order to delineate the genetic contribution of causative variants in cohesin complex genes as well as novel candidate genes, genotype-phenotype correlations, and the utility of genome sequencing in understanding the mutational landscape in this population.

10 Oct 2019·ACS Medicinal Chemistry LettersQ3 · MEDICINE

Dual Inhibition of TAF1 and BET Bromodomains from the BI-2536 Kinase Inhibitor Scaffold

Q3 · MEDICINE

Article

Author: Dhe-Paganon, Sirano ; Gray, Nathanael S. ; Ferguson, Fleur M. ; Remillard, David ; Bradner, James E. ; Seo, Hyuk-Soo ; Buckley, Dennis L.

Recent reports have highlighted the dual bromodomains of TAF1 (TAF1(1,2)) as synergistic with BET inhibition in cellular cancer models, engendering interest in TAF/BET polypharmacology. Here, we examine structure activity relationships within the BI-2536 PLK1 kinase inhibitor scaffold, previously reported to bind BRD4. We examine binding by this ligand to TAF1(2) and apply structure guided design strategies to discriminate binding to both the PLK1 kinase and BRD4(1) bromodomain while retaining activity on TAF1(2). Through this effort we discover potent dual inhibitors of TAF1(2)/BRD4(1), as well as biased derivatives showing marked TAF1 selectivity. We resolve X-ray crystallographic data sets to examine the mechanisms of the observed TAF1 selectivity and to provide a resource for further development of this scaffold.

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