Last update 01 Nov 2024

ALK x BRD4

Last update 01 Nov 2024

Basic Info

Related Targets

ALKBRD4

Drugs associated with ALK x BRD4

CCT-368408

Target

ALK x BRD4

Mechanism

ALK inhibitors [+1]

Active Org.-

Originator Org.

The Institute of Cancer Research: Royal Cancer Hospital

Active Indication-

Inactive Indication

Neuroblastoma

Drug Highest PhaseDiscontinued

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with ALK x BRD4

100 Translational Medicine associated with ALK x BRD4

0 Patents (Medical) associated with ALK x BRD4

Literatures (Medical) associated with ALK x BRD4

01 Apr 2021·Lung CancerQ2 · MEDICINE

Revealing the BRD4-NOTCH3 fusion: A novel hill in the cancer landscape

Q2 · MEDICINE

Article

Author: Pavlick, Dean C ; de Castro, Gilberto ; Amano, Mariane Tami ; Testagrossa, Leonardo ; Costa, Fabiano de Almeida ; Asprino, Paula Fontes ; Masotti, Cibele

OBJECTIVESGene fusions are becoming more evident in cancer scenario for either being the driver alterations, or for the great therapeutic target potential in many cases. Our aim was to characterize the BRD4-NOTCH3 fusion correlating with clinical features, and to determine the frequency of this fusion in the oncological population.MATERIAL AND METHODSOne patient diagnosed with lung adenocarcinoma at Hospital Sírio-Libanês (Brazil) was included. Foundation Medicine database was searched for all BRD4-NOTCH3 fusions among 233,804 specimens.RESULTSA 76-year-old male patient was diagnosed with lung adenocarcinoma. Molecular assessments demonstrated negative ALK and EGFR, with PD-L1 expression positive by 60 %. He was treated with first line chemotherapy and second line immunotherapy. Subsequent treatments resume re-exposures to chemotherapy with poor responses. A next-generation sequencing (NGS) based assay was performed in the tumor biopsy, revealing mainly mutation in STK11, microsatellite stability, TMB-intermediate, MYC amplification and a BRD4-NOTCH3 fusion. The breakpoint analysis of this fusion indicates that BRD4 active domains are preserved, suggesting that it maintained DNA binding activity, as well as its capacity to be halt by BET inhibitors. Foundation Medicine database was searched for all BRD4-NOTCH3 fusions among more than 230-thousand specimens and it was found in 87 new cases in a rate of 0.04 % occurrence in solid tumors, predominately in gynecological cancers. The same rate was found when we analyzed a different dataset.CONCLUSIONIn conclusion, this is the first report of the BRD4-NOTCH3 gene fusion associated with clinical characterization and, although rare, the occurrence of this fusion is constant in different population. Our data suggest that this fusion has great potential to targeted-therapy.

14 Mar 2019·Journal of Medicinal ChemistryQ1 · MEDICINE

Designing Dual Inhibitors of Anaplastic Lymphoma Kinase (ALK) and Bromodomain-4 (BRD4) by Tuning Kinase Selectivity

Q1 · MEDICINE

Article

Author: Knapp, Stefan ; Tucker, Elizabeth ; Strebhardt, Klaus ; Heidenreich, David ; Hoelder, Swen ; Chesler, Louis ; Raab, Monika ; Bellenie, Benjamin ; Watts, Ellen

Concomitant inhibition of anaplastic lymphoma kinase (ALK) and bromodomain-4 (BRD4) is a potential therapeutic strategy for targeting two key oncogenic drivers that co-segregate in a significant fraction of high-risk neuroblastoma patients, mutation of ALK and amplification of MYCN. Starting from known dual polo-like kinase (PLK)-1-BRD4 inhibitor BI-2536, we employed structure-based design to redesign this series toward compounds with a dual ALK-BRD4 profile. These efforts led to compound ( R)-2-((2-ethoxy-4-(1-methylpiperidin-4-yl)phenyl)amino)-7-ethyl-5-methyl-8-((4-methylthiophen-2-yl)methyl)-7,8-dihydropteridin-6(5 H)-one (16k) demonstrating improved ALK activity and significantly reduced PLK-1 activity, while maintaining BRD4 activity and overall kinome selectivity. We demonstrate the compounds' on-target engagement with ALK and BRD4 in cells as well as favorable broad kinase and bromodomain selectivity.

19 Jan 2018·Oncotarget

Natural and molecular history of prolactinoma: insights from aPrlr-/– mouse model

Article

Author: Martin, Agnès ; Binart, Nadine ; Villa, Chiara ; Young, Jacques ; Auguste, Aurélie ; Lamothe, Sophie ; Guillou, Anne ; Bernard, Valérie ; Caburet, Sandrine ; Veitia, Reiner A.

Lactotroph adenoma, also called prolactinoma, is the most common pituitary tumor but little is known about its pathogenesis. Mouse models of prolactinoma can be useful to better understand molecular mechanisms involved in abnormal lactotroph cell proliferation and secretion. We have previously developed a prolactin receptor deficient (Prlr^-/- ) mouse, which develops prolactinoma. The present study aims to explore the natural history of prolactinoma formation in Prlr^-/- mice, using hormonal, radiological, histological and molecular analyses to uncover mechanisms involved in lactotroph adenoma development. Prlr^-/- females develop large secreting prolactinomas from 12 months of age, with a penetrance of 100%, mimicking human aggressive densely granulated macroprolactinoma, which is a highly secreting subtype. Mean blood PRL measurements reach 14 902 ng/mL at 24 months in Prlr^-/- females while PRL levels were below 15 ng/mL in control mice (p < 0.01). By comparing pituitary microarray data of Prlr^-/- mice and an estrogen-induced prolactinoma model in ACI rats, we pinpointed 218 concordantly differentially expressed (DE) genes involved in cell cycle, mitosis, cell adhesion molecules, dopaminergic synapse and estrogen signaling. Pathway/gene-set enrichment analyses suggest that the transcriptomic dysregulation in both models of prolactinoma might be mediated by a limited set of transcription factors (i.e., STAT5, STAT3, AhR, ESR1, BRD4, CEBPD, YAP, FOXO1) and kinases (i.e., JAK2, AKT1, BRAF, BMPR1A, CDK8, HUNK, ALK, FGFR1, ILK). Our experimental results and their bioinformatic analysis provide insights into early genomic changes in murine models of the most frequent human pituitary tumor.

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