Recent Advances in Dual BRD4‐Kinase Inhibitors Based on Polypharmacology

Differential BET Bromodomain Inhibition by Dihydropteridinone and Pyrimidodiazepinone Kinase Inhibitors

(2021) Rezaul Md Karim et al.   JOURNAL OF MEDICINAL CHEMISTRY

Macrocyclization as a Source of Desired Polypharmacology. Discovery of Triple PI3K/mTOR/PIM Inhibitors

(2021) Sonia Martínez-González et al.   ACS Medicinal Chemistry Letters

Dual-target kinase drug design: Current strategies and future directions in cancer therapy

(2020) Dejuan Sun et al.   EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY

Design, synthesis, and biological evaluation of 4,5-dihydro-[1,2,4]triazolo[4,3-f]pteridine derivatives as novel dual-PLK1/BRD4 inhibitors

(2020) Ning-Yu Wang et al.   EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY

Novel strategies targeting bromodomain-containing protein 4 (BRD4) for cancer drug discovery

(2020) Dailin Liang et al.   EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY

Discovery of 8-Methyl-pyrrolo[1,2-a]pyrazin-1(2H)-one Derivatives as Highly Potent and Selective Bromodomain and Extra-Terminal (BET) Bromodomain Inhibitors

(2020) Zizhou Li et al.   JOURNAL OF MEDICINAL CHEMISTRY

Rational Design and Evaluation of 6-(Pyrimidin-2-ylamino)-3,4-dihydroquinoxalin-2(1H)-ones as Polypharmacological Inhibitors of BET and Kinases

(2020) Kaikai Lv et al.   JOURNAL OF MEDICINAL CHEMISTRY

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

(2019) Ellen Watts et al.   JOURNAL OF MEDICINAL CHEMISTRY

Systematically Mitigating the p38α Activity of Triazole-based BET Inhibitors

(2019) Angela S. Carlson et al.   ACS Medicinal Chemistry Letters

Synergistic activity of BET inhibitor BI 894999 with PLK inhibitor volasertib in AML in vitro and in vivo

(2018) Ulrike Tontsch-Grunt et al.   CANCER LETTERS

Plk1 Inhibition Enhances the Efficacy of BET Epigenetic Reader Blockade in Castration-Resistant Prostate Cancer

(2018) Fengyi Mao et al.   MOLECULAR CANCER THERAPEUTICS

Structural and Atropisomeric Factors Governing the Selectivity of Pyrimido-benzodiazipinones as Inhibitors of Kinases and Bromodomains

(2018) Jinhua Wang et al.   ACS Chemical Biology

Polypharmacology by Design: A Medicinal Chemist’s Perspective on Multitargeting Compounds

(2018) Ewgenij Proschak et al.   JOURNAL OF MEDICINAL CHEMISTRY

Structure-Guided Design and Development of Potent and Selective Dual Bromodomain 4 (BRD4)/Polo-like Kinase 1 (PLK1) Inhibitors

(2018) Shuai Liu et al.   JOURNAL OF MEDICINAL CHEMISTRY

Molecular Basis for the N-Terminal Bromodomain and Extra Terminal (BET) Family Selectivity of a Dual Kinase-Bromodomain Inhibitor

(2018) Anand Divakaran et al.   JOURNAL OF MEDICINAL CHEMISTRY

Drug Discovery Targeting Bromodomain-Containing Protein 4

(2017) Zhiqing Liu et al.   JOURNAL OF MEDICINAL CHEMISTRY

Potent Dual BET Bromodomain-Kinase Inhibitors as Value-Added Multitargeted Chemical Probes and Cancer Therapeutics

(2017) Stuart W. Ember et al.   MOLECULAR CANCER THERAPEUTICS

Dual-activity PI3K–BRD4 inhibitor for the orthogonal inhibition of MYC to block tumor growth and metastasis

(2017) Forest H. Andrews et al.   PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

Small-Molecule PROTACS: New Approaches to Protein Degradation

(2016) Momar Toure et al.   ANGEWANDTE CHEMIE-INTERNATIONAL EDITION

Structure-based optimization leads to the discovery of NSC765844, a highly potent, less toxic and orally efficacious dual PI3K/mTOR inhibitor

(2016) Jinsong Han et al.   EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY

Bromodomain and extra-terminal (BET) family proteins: New therapeutic targets in major diseases

(2016) Balasundaram Padmanabhan et al.   JOURNAL OF BIOSCIENCES

Dual Kinase-Bromodomain Inhibitors in Anticancer Drug Discovery: A Structural and Pharmacological Perspective

(2016) Luca Carlino et al.   JOURNAL OF MEDICINAL CHEMISTRY

Identification of a Benzoisoxazoloazepine Inhibitor (CPI-0610) of the Bromodomain and Extra-Terminal (BET) Family as a Candidate for Human Clinical Trials

(2016) Brian K. Albrecht et al.   JOURNAL OF MEDICINAL CHEMISTRY

Single Agent and Synergistic Activity of the "First-in-Class" Dual PI3K/BRD4 Inhibitor SF1126 with Sorafenib in Hepatocellular Carcinoma

(2016) A. R. Singh et al.   MOLECULAR CANCER THERAPEUTICS

AZD5153: A Novel Bivalent BET Bromodomain Inhibitor Highly Active against Hematologic Malignancies

(2016) G. W. Rhyasen et al.   MOLECULAR CANCER THERAPEUTICS

Response and resistance to BET bromodomain inhibitors in triple-negative breast cancer

(2016) Shaokun Shu et al.   NATURE

Dual Screening of BPTF and Brd4 Using Protein-Observed Fluorine NMR Uncovers New Bromodomain Probe Molecules

(2015) Andrew K. Urick et al.   ACS Chemical Biology

Synergistic activity of BET protein antagonist-based combinations in mantle cell lymphoma cells sensitive or resistant to ibrutinib

(2015) B. Sun et al.   BLOOD

Kinase and BET Inhibitors Together Clamp Inhibition of PI3K Signaling and Overcome Resistance to Therapy

(2015) Elias E. Stratikopoulos et al.   CANCER CELL

The BET Bromodomain Inhibitor OTX015 Affects Pathogenetic Pathways in Preclinical B-cell Tumor Models and Synergizes with Targeted Drugs

(2015) M. Boi et al.   CLINICAL CANCER RESEARCH

Disrupting Acetyl-Lysine Recognition: Progress in the Development of Bromodomain Inhibitors

(2015) F. Anthony Romero et al.   JOURNAL OF MEDICINAL CHEMISTRY

Transcriptional plasticity promotes primary and acquired resistance to BET inhibition

(2015) Philipp Rathert et al.   NATURE

BET inhibitor resistance emerges from leukaemia stem cells

(2015) Chun Yew Fong et al.   NATURE

Beating the odds: BETs in disease

(2015) Chen-Yi Wang et al.   TRENDS IN BIOCHEMICAL SCIENCES

BRD4 Structure–Activity Relationships of Dual PLK1 Kinase/BRD4 Bromodomain Inhibitor BI-2536

(2015) Lijia Chen et al.   ACS Medicinal Chemistry Letters

BET inhibitor OTX015 targets BRD2 and BRD4 and decreases c-MYC in acute leukemia cells

(2015) Marie-Magdelaine Coudé et al.   Oncotarget

BET inhibitors induce apoptosis through a MYC independent mechanism and synergise with CDK inhibitors to kill osteosarcoma cells

(2015) Emma K Baker et al.   Scientific Reports

Large-Scale Computational Screening Identifies First in Class Multitarget Inhibitor of EGFR Kinase and BRD4

(2015) Bryce K. Allen et al.   Scientific Reports

Inhibition of Lapatinib-Induced Kinome Reprogramming in ERBB2-Positive Breast Cancer by Targeting BET Family Bromodomains

(2015) Timothy J. Stuhlmiller et al.   Cell Reports

INCB16562, a JAK1/2 Selective Inhibitor, Is Efficacious against Multiple Myeloma Cells and Reverses the Protective Effects of Cytokine and Stromal Cell Support

(2015) Jun Li et al.   NEOPLASIA

Acetyl-lysine Binding Site of Bromodomain-Containing Protein 4 (BRD4) Interacts with Diverse Kinase Inhibitors

(2014) Stuart W. J. Ember et al.   ACS Chemical Biology

Disrupting the Interaction of BRD4 with Diacetylated Twist Suppresses Tumorigenesis in Basal-like Breast Cancer

(2014) Jian Shi et al.   CANCER CELL

Synergistic effect of JQ1 and rapamycin for treatment of human osteosarcoma

(2014) Dhong Hyun Lee et al.   INTERNATIONAL JOURNAL OF CANCER

Targeting STAT5 in Hematologic Malignancies through Inhibition of the Bromodomain and Extra-Terminal (BET) Bromodomain Protein BRD2

(2014) S. Liu et al.   MOLECULAR CANCER THERAPEUTICS

BET Protein Antagonist JQ1 Is Synergistically Lethal with FLT3 Tyrosine Kinase Inhibitor (TKI) and Overcomes Resistance to FLT3-TKI in AML Cells Expressing FLT-ITD

(2014) W. Fiskus et al.   MOLECULAR CANCER THERAPEUTICS

Dual kinase-bromodomain inhibitors for rationally designed polypharmacology

(2014) Pietro Ciceri et al.   Nature Chemical Biology

Targeting bromodomains: epigenetic readers of lysine acetylation

(2014) Panagis Filippakopoulos et al.   NATURE REVIEWS DRUG DISCOVERY

Blockade of oncogenic I B kinase activity in diffuse large B-cell lymphoma by bromodomain and extraterminal domain protein inhibitors

(2014) M. Ceribelli et al.   PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

The bromodomain and extra-terminal inhibitor CPI203 enhances the antiproliferative effects of rapamycin on human neuroendocrine tumors

(2014) C Wong et al.   Cell Death & Disease

The Commonly Used PI3-Kinase Probe LY294002 Is an Inhibitor of BET Bromodomains

(2013) Antje Dittmann et al.   ACS Chemical Biology

Cyclin-Dependent Kinase Inhibitor Dinaciclib Interacts with the Acetyl-Lysine Recognition Site of Bromodomains

(2013) Mathew P. Martin et al.   ACS Chemical Biology

A randomized, open-label, phase I/II trial to investigate the maximum tolerated dose of the Polo-like kinase inhibitor BI 2536 in elderly patients with refractory/relapsed acute myeloid leukaemia

(2013) Carsten Müller-Tidow et al.   BRITISH JOURNAL OF HAEMATOLOGY

A multi-histology trial of fostamatinib in patients with advanced colorectal, non-small cell lung, head and neck, thyroid, and renal cell carcinomas, and pheochromocytomas

(2013) Sook Ryun Park et al.   CANCER CHEMOTHERAPY AND PHARMACOLOGY

BET bromodomain-targeting compounds reactivate HIV from latency via a Tat-independent mechanism

(2013) Daniela Boehm et al.   CELL CYCLE

Sensitivity and resistance of JAK2 inhibitors to myeloproliferative neoplasms

(2013) Neha Bhagwat et al.   INTERNATIONAL JOURNAL OF HEMATOLOGY

Discovery of Epigenetic Regulator I-BET762: Lead Optimization to Afford a Clinical Candidate Inhibitor of the BET Bromodomains

(2013) Olivier Mirguet et al.   JOURNAL OF MEDICINAL CHEMISTRY

Synthesis and Cancer Stem Cell-Based Activity of Substituted 5-Morpholino-7H-thieno[3,2-b]pyran-7-ones Designed as Next Generation PI3K Inhibitors

(2013) Guillermo A. Morales et al.   JOURNAL OF MEDICINAL CHEMISTRY

X-ray Crystal Structure of ERK5 (MAPK7) in Complex with a Specific Inhibitor

(2013) Jonathan M. Elkins et al.   JOURNAL OF MEDICINAL CHEMISTRY

JAK inhibitors suppress t(8;21) fusion protein-induced leukemia

(2013) M-C Lo et al.   LEUKEMIA

RVX-208, an inhibitor of BET transcriptional regulators with selectivity for the second bromodomain

(2013) S. Picaud et al.   PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

Targeting MYCN in Neuroblastoma by BET Bromodomain Inhibition

(2013) Alexandre Puissant et al.   Cancer Discovery

Identification of a novel series of BET family bromodomain inhibitors: Binding mode and profile of I-BET151 (GSK1210151A)

(2012) Jonathan Seal et al.   BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

The ALKF1174L Mutation Potentiates the Oncogenic Activity of MYCN in Neuroblastoma

(2012) Teeara Berry et al.   CANCER CELL

Histone Recognition and Large-Scale Structural Analysis of the Human Bromodomain Family

(2012) Panagis Filippakopoulos et al.   CELL

A Phase I Open-Label Dose-Escalation Study of Intravenous BI 2536 Together With Pemetrexed in Previously Treated Patients With Non–Small-Cell Lung Cancer

(2012) Peter M. Ellis et al.   Clinical Lung Cancer

Validation of ITD mutations in FLT3 as a therapeutic target in human acute myeloid leukaemia

(2012) Catherine C. Smith et al.   NATURE

Epigenetic protein families: a new frontier for drug discovery

(2012) Cheryl H. Arrowsmith et al.   NATURE REVIEWS DRUG DISCOVERY

Cyclin-dependent kinase inhibitors move into Phase III

(2012) Malini Guha   NATURE REVIEWS DRUG DISCOVERY

BRD4 is an atypical kinase that phosphorylates Serine2 of the RNA Polymerase II carboxy-terminal domain

(2012) B. N. Devaiah et al.   PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

Kinase inhibitors: a new class of antirheumatic drugs

(2012) Vasileios Kyttaris   Drug Design Development and Therapy

Reactivation of Latent HIV-1 by Inhibition of BRD4

(2012) Jian Zhu et al.   Cell Reports

BET Bromodomain Inhibition as a Therapeutic Strategy to Target c-Myc

(2011) Jake E. Delmore et al.   CELL

Bromodomains as therapeutic targets

(2011) Susanne Muller et al.   EXPERT REVIEWS IN MOLECULAR MEDICINE

Safety and Efficacy of TG101348, a Selective JAK2 Inhibitor, in Myelofibrosis

(2011) Animesh Pardanani et al.   JOURNAL OF CLINICAL ONCOLOGY

Discovery and Characterization of Small Molecule Inhibitors of the BET Family Bromodomains

(2011) Chun-wa Chung et al.   JOURNAL OF MEDICINAL CHEMISTRY

Opportunities and Challenges in the Development of Experimental Drug Combinations for Cancer

(2011) R. W. Humphrey et al.   JNCI-Journal of the National Cancer Institute

Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia

(2011) Mark A. Dawson et al.   NATURE

Targeting MYC dependence in cancer by inhibiting BET bromodomains

(2011) J. A. Mertz et al.   PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

Discovery of Pyridazinopyridinones as Potent and Selective p38 Mitogen-Activated Protein Kinase Inhibitors

(2010) Bin Wu et al.   JOURNAL OF MEDICINAL CHEMISTRY

Dinaciclib (SCH 727965), a Novel and Potent Cyclin-Dependent Kinase Inhibitor

(2010) David Parry et al.   MOLECULAR CANCER THERAPEUTICS

Suppression of inflammation by a synthetic histone mimic

(2010) Edwige Nicodeme et al.   NATURE

Selective inhibition of BET bromodomains

(2010) Panagis Filippakopoulos et al.   NATURE

Discovery of Dinaciclib (SCH 727965): A Potent and Selective Inhibitor of Cyclin-Dependent Kinases

(2010) Kamil Paruch et al.   ACS Medicinal Chemistry Letters

Polo-like kinase 1 is overexpressed in acute myeloid leukemia and its inhibition preferentially targets the proliferation of leukemic cells

(2009) A. G. Renner et al.   BLOOD

BI 6727, A Polo-like Kinase Inhibitor with Improved Pharmacokinetic Profile and Broad Antitumor Activity

(2009) D. Rudolph et al.   CLINICAL CANCER RESEARCH

Structures of the Dual Bromodomains of the P-TEFb-activating Protein Brd4 at Atomic Resolution

(2009) Friederike Vollmuth et al.   JOURNAL OF BIOLOGICAL CHEMISTRY

Regulation of Aurora B Expression by the Bromodomain Protein Brd4

(2009) J. You et al.   MOLECULAR AND CELLULAR BIOLOGY

Brd4 Marks Select Genes on Mitotic Chromatin and Directs Postmitotic Transcription

(2009) Anup Dey et al.   MOLECULAR BIOLOGY OF THE CELL

Brd4 Coactivates Transcriptional Activation of NF- B via Specific Binding to Acetylated RelA

(2008) B. Huang et al.   MOLECULAR AND CELLULAR BIOLOGY