Killing Two Cells with One Stone: Pharmacologic BCL-2 Family Targeting for Cancer Cell Death and Immune Modulation

A BH3 Mimetic for Killing Cancer Cells

(2016) Douglas R. Green   CELL

A phase II trial of the BCL-2 homolog domain 3 mimetic AT-101 in combination with docetaxel for recurrent, locally advanced, or metastatic head and neck cancer

(2016) Paul L. Swiecicki et al.   INVESTIGATIONAL NEW DRUGS

Discovery of 2-Indole-acylsulfonamide Myeloid Cell Leukemia 1 (Mcl-1) Inhibitors Using Fragment-Based Methods

(2016) Nicholas F. Pelz et al.   JOURNAL OF MEDICINAL CHEMISTRY

Targeting BCL2 with Venetoclax in Relapsed Chronic Lymphocytic Leukemia

(2016) Andrew W. Roberts et al.   NEW ENGLAND JOURNAL OF MEDICINE

Distinctive Expression of Bcl-2 Factors in Regulatory T Cells Determines a Pharmacological Target to Induce Immunological Tolerance

(2016) Sarah Sharon Gabriel et al.   Frontiers in Immunology

Phase 1 study of the safety, pharmacokinetics, and antitumour activity of the BCL2 inhibitor navitoclax in combination with rituximab in patients with relapsed or refractory CD20+lymphoid malignancies

(2015) Andrew W. Roberts et al.   BRITISH JOURNAL OF HAEMATOLOGY

Increased lymphocyte apoptosis in mouse models of colitis upon ABT-737 treatment is dependent upon BIM expression

(2015) C. Lutz et al.   CLINICAL AND EXPERIMENTAL IMMUNOLOGY

Attacking cancer's Achilles heel: antagonism of anti-apoptotic BCL-2 family members

(2015) Joseph T. Opferman   FEBS Journal

Potent and Specific Peptide Inhibitors of Human Pro-Survival Protein Bcl-x L

(2015) Sanjib Dutta et al.   JOURNAL OF MOLECULAR BIOLOGY

MCL-1 Is a Key Determinant of Breast Cancer Cell Survival: Validation of MCL-1 Dependency Utilizing a Highly Selective Small Molecule Inhibitor

(2015) Y. Xiao et al.   MOLECULAR CANCER THERAPEUTICS

Potent and selective small-molecule MCL-1 inhibitors demonstrate on-target cancer cell killing activity as single agents and in combination with ABT-263 (navitoclax)

(2015) J D Leverson et al.   Cell Death & Disease

Loss in MCL-1 function sensitizes non-Hodgkin’s lymphoma cell lines to the BCL-2-selective inhibitor venetoclax (ABT-199)

(2015) D C Phillips et al.   Blood Cancer Journal

ABT-199 mediated inhibition of BCL-2 as a novel therapeutic strategy in T-cell acute lymphoblastic leukemia

(2014) S. Peirs et al.   BLOOD

The Anti-Apoptotic Bcl-2 Family Member Mcl-1 Promotes T Lymphocyte Survival at Multiple Stages

(2014) I. Dzhagalov et al.   JOURNAL OF IMMUNOLOGY

Pan-Bcl-2 Inhibitor, GX15-070 (Obatoclax), Decreases Human T Regulatory Lymphocytes while Preserving Effector T Lymphocytes: A Rationale for Its Use in Combination Immunotherapy

(2014) P. S. Kim et al.   JOURNAL OF IMMUNOLOGY

3-Substituted-N-(4-Hydroxynaphthalen-1-yl)arylsulfonamides as a Novel Class of Selective Mcl-1 Inhibitors: Structure-Based Design, Synthesis, SAR, and Biological Evaluation

(2014) Fardokht A. Abulwerdi et al.   JOURNAL OF MEDICINAL CHEMISTRY

Both leukaemic and normal peripheral B lymphoid cells are highly sensitive to the selective pharmacological inhibition of prosurvival Bcl-2 with ABT-199

(2014) S L Khaw et al.   LEUKEMIA

A phase I/II study of the pan Bcl-2 inhibitor obatoclax mesylate plus bortezomib for relapsed or refractory mantle cell lymphoma

(2014) André Goy et al.   LEUKEMIA & LYMPHOMA

BM-1197: A Novel and Specific Bcl-2/Bcl-xL Inhibitor Inducing Complete and Long-Lasting Tumor Regression In Vivo

(2014) Longchuan Bai et al.   PLoS One

A Multicenter Phase I/II Study of Obatoclax Mesylate Administered as a 3- or 24-Hour Infusion in Older Patients with Previously Untreated Acute Myeloid Leukemia

(2014) Aaron D. Schimmer et al.   PLoS One

Impact of conditional deletion of the pro-apoptotic BCL-2 family member BIM in mice

(2014) M J Herold et al.   Cell Death & Disease

Discovery of a Potent and Selective BCL-XL Inhibitor with in Vivo Activity

(2014) Zhi-Fu Tao et al.   ACS Medicinal Chemistry Letters

Getting away with murder: how does the BCL-2 family of proteins kill with immunity?

(2013) Thibaud T. Renault et al.   Annals of the New York Academy of Sciences

Potent obatoclax cytotoxicity and activation of triple death mode killing across infant acute lymphoblastic leukemia

(2013) K. A. Urtishak et al.   BLOOD

ABT-199 selectively inhibits BCL2 but not BCL2L1 and efficiently induces apoptosis of chronic lymphocytic leukaemic cells but not platelets

(2013) Meike Vogler et al.   BRITISH JOURNAL OF HAEMATOLOGY

A phase 1 study of the BCL2-targeted deoxyribonucleic acid inhibitor (DNAi) PNT2258 in patients with advanced solid tumors

(2013) Anthony W. Tolcher et al.   CANCER CHEMOTHERAPY AND PHARMACOLOGY

Combining CAR T cells and the Bcl-2 family apoptosis inhibitor ABT-737 for treating B-cell malignancy

(2013) S C H Karlsson et al.   CANCER GENE THERAPY

Novel Small-Molecule Inhibitors of Bcl-XL to Treat Lung Cancer

(2013) D. Park et al.   CANCER RESEARCH

Multimodal Interaction with BCL-2 Family Proteins Underlies the Proapoptotic Activity of PUMA BH3

(2013) Amanda L. Edwards et al.   CHEMISTRY & BIOLOGY

Pro-Apoptotic Protein Noxa Regulates Memory T Cell Population Size and Protects against Lethal Immunopathology

(2013) F. M. Wensveen et al.   JOURNAL OF IMMUNOLOGY

BH3 profiling in whole cells by fluorimeter or FACS

(2013) Jeremy Ryan et al.   METHODS

The novel BH3 α-helix mimetic JY-1-106 induces apoptosis in a subset of cancer cells (lung cancer, colon cancer and mesothelioma) by disrupting Bcl-xL and Mcl-1 protein–protein interactions with Bak

(2013) Xiaobo Cao et al.   Molecular Cancer

Structure-guided design of a selective BCL-XL inhibitor

(2013) Guillaume Lessene et al.   Nature Chemical Biology

Mcl-1 is essential for the survival of plasma cells

(2013) Victor Peperzak et al.   NATURE IMMUNOLOGY

Antiapoptotic Mcl-1 is critical for the survival and niche-filling capacity of Foxp3+ regulatory T cells

(2013) Wim Pierson et al.   NATURE IMMUNOLOGY

ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets

(2013) Andrew J Souers et al.   NATURE MEDICINE

Control of apoptosis by the BCL-2 protein family: implications for physiology and therapy

(2013) Peter E. Czabotar et al.   NATURE REVIEWS MOLECULAR CELL BIOLOGY

Selective BCL-2 Inhibition by ABT-199 Causes On-Target Cell Death in Acute Myeloid Leukemia

(2013) R. Pan et al.   Cancer Discovery

Targeting antiapoptotic A1/Bfl-1 by in vivo RNAi reveals multiple roles in leukocyte development in mice

(2012) E. Ottina et al.   BLOOD

A Competitive Stapled Peptide Screen Identifies a Selective Small Molecule that Overcomes MCL-1-Dependent Leukemia Cell Survival

(2012) Nicole A. Cohen et al.   CHEMISTRY & BIOLOGY

Discovery of Marinopyrrole A (Maritoclax) as a Selective Mcl-1 Antagonist that Overcomes ABT-737 Resistance by Binding to and Targeting Mcl-1 for Proteasomal Degradation

(2012) Kenichiro Doi et al.   JOURNAL OF BIOLOGICAL CHEMISTRY

A stapled BIM peptide overcomes apoptotic resistance in hematologic cancers

(2012) James L. LaBelle et al.   JOURNAL OF CLINICAL INVESTIGATION

Rational Design of Proteolytically Stable, Cell-Permeable Peptide-Based Selective Mcl-1 Inhibitors

(2012) Avinash Muppidi et al.   JOURNAL OF THE AMERICAN CHEMICAL SOCIETY

Direct and selective small-molecule activation of proapoptotic BAX

(2012) Evripidis Gavathiotis et al.   Nature Chemical Biology

Resistance to ABT-737 in activated T lymphocytes: molecular mechanisms and reversibility by inhibition of the calcineurin–NFAT pathway

(2012) P E Cippà et al.   Cell Death & Disease

Regulation of memory B-cell survival by the BH3-only protein Puma

(2011) C. Clybouw et al.   BLOOD

BH3-only protein Noxa regulates apoptosis in activated B cells and controls high-affinity antibody formation

(2011) F. M. Wensveen et al.   BLOOD

Targeting Bcl-2 family proteins in adult T-cell leukemia/lymphoma: In vitro and in vivo effects of the novel Bcl-2 family inhibitor ABT-737

(2011) Kenji Ishitsuka et al.   CANCER LETTERS

A novel Bim-BH3-derived Bcl-XL inhibitor: Biochemical characterization, in vitro, in vivo and ex-vivo anti-leukemic activity

(2011) Raffaella Ponassi et al.   CELL CYCLE

Substantial Susceptibility of Chronic Lymphocytic Leukemia to BCL2 Inhibition: Results of a Phase I Study of Navitoclax in Patients With Relapsed or Refractory Disease

(2011) Andrew W. Roberts et al.   JOURNAL OF CLINICAL ONCOLOGY

Evaluation of the Bcl-2 family antagonist ABT-737 in collagen-induced arthritis

(2011) Kate E. Lawlor et al.   JOURNAL OF LEUKOCYTE BIOLOGY

A Phase II Study of AT-101 (Gossypol) in Chemotherapy-Sensitive Recurrent Extensive-Stage Small Cell Lung Cancer

(2011) Maria Q. Baggstrom et al.   Journal of Thoracic Oncology

Apogossypol derivative BI-97C1 (Sabutoclax) targeting Mcl-1 sensitizes prostate cancer cells to mda-7/IL-24-mediated toxicity

(2011) R. Dash et al.   PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

The BH3-mimetic ABT-737 inhibits allogeneic immune responses

(2011) Pietro E. Cippà et al.   TRANSPLANT INTERNATIONAL

An Optically Pure Apogossypolone Derivative as Potent Pan-Active Inhibitor of Anti-Apoptotic Bcl-2 Family Proteins

(2011) Jun Wei et al.   Frontiers in Oncology

BH3-only proteins: Orchestrators of apoptosis

(2010) Aisha Shamas-Din et al.   BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH

A role for proapoptotic Bax and Bak in T-cell differentiation and transformation

(2010) S. Biswas et al.   BLOOD

Acquired resistance to ABT-737 in lymphoma cells that up-regulate MCL-1 and BFL-1

(2010) D. Yecies et al.   BLOOD

Phase II Study of Obatoclax Mesylate (GX15-070), a Small-Molecule BCL-2 Family Antagonist, for Patients With Myelofibrosis

(2010) Sameer A. Parikh et al.   Clinical Lymphoma Myeloma & Leukemia

Thrombocytopenia Exacerbates Cholestasis-Induced Liver Fibrosis in Mice

(2010) Takahiro Kodama et al.   GASTROENTEROLOGY

Apoptosis Threshold Set by Noxa and Mcl-1 after T Cell Activation Regulates Competitive Selection of High-Affinity Clones

(2010) Felix M. Wensveen et al.   IMMUNITY

Effect of a small molecule BCL-2 inhibitor on immune function and use with a recombinant vaccine

(2010) Benedetto Farsaci et al.   INTERNATIONAL JOURNAL OF CANCER

A novel BH3 mimetic S1 potently induces Bax/Bak-dependent apoptosis by targeting both Bcl-2 and Mcl-1

(2010) Zhichao Zhang et al.   INTERNATIONAL JOURNAL OF CANCER

The BH3 α-Helical Mimic BH3-M6 Disrupts Bcl-XL, Bcl-2, and MCL-1 Protein-Protein Interactions with Bax, Bak, Bad, or Bim and Induces Apoptosis in a Bax- and Bim-dependent Manner

(2010) Aslamuzzaman Kazi et al.   JOURNAL OF BIOLOGICAL CHEMISTRY

The BH3-Mimetic ABT-737 Induces Mast Cell Apoptosis In Vitro and In Vivo: Potential for Therapeutics

(2010) M. Karlberg et al.   JOURNAL OF IMMUNOLOGY

Bim Dictates Naive CD4 T Cell Lifespan and the Development of Age-Associated Functional Defects

(2010) H. Tsukamoto et al.   JOURNAL OF IMMUNOLOGY

BI-97C1, an Optically Pure Apogossypol Derivative as Pan-Active Inhibitor of Antiapoptotic B-Cell Lymphoma/Leukemia-2 (Bcl-2) Family Proteins

(2010) Jun Wei et al.   JOURNAL OF MEDICINAL CHEMISTRY

Navitoclax, a targeted high-affinity inhibitor of BCL-2, in lymphoid malignancies: a phase 1 dose-escalation study of safety, pharmacokinetics, pharmacodynamics, and antitumour activity

(2010) Wyndham H Wilson et al.   LANCET ONCOLOGY

The MCL-1 BH3 helix is an exclusive MCL-1 inhibitor and apoptosis sensitizer

(2010) Michelle L Stewart et al.   Nature Chemical Biology

BH3 mimetics antagonizing restricted prosurvival Bcl-2 proteins represent another class of selective immune modulatory drugs

(2010) E. M. Carrington et al.   PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

BID, BIM, and PUMA Are Essential for Activation of the BAX- and BAK-Dependent Cell Death Program

(2010) D. Ren et al.   SCIENCE

Mcl-1 Is Essential for Germinal Center Formation and B Cell Memory

(2010) I. Vikstrom et al.   SCIENCE

A survey of the anti-apoptotic Bcl-2 subfamily expression in cancer types provides a platform to predict the efficacy of Bcl-2 antagonists in cancer therapy

(2010) W J Placzek et al.   Cell Death & Disease

The p53-Target Gene Puma Drives Neutrophil-Mediated Protection against Lethal Bacterial Sepsis

(2010) Sean P. Garrison et al.   PLoS Pathogens

Gossypol induced apoptosis of polymorphonuclear leukocytes and monocytes: Involvement of mitochondrial pathway and reactive oxygen species

(2009) Martha Barba-Barajas et al.   IMMUNOPHARMACOLOGY AND IMMUNOTOXICOLOGY

The Bcl-2 Family Antagonist ABT-737 Significantly Inhibits Multiple Animal Models of Autoimmunity

(2009) P. D. Bardwell et al.   JOURNAL OF IMMUNOLOGY

Phase III randomised study of dexamethasone with or without oblimersen sodium for patients with advanced multiple myeloma

(2009) Asher A. Chanan-Khan et al.   LEUKEMIA & LYMPHOMA

The Bcl-2 Homology Domain 3 Mimetic ABT-737 Targets the Apoptotic Machinery in Acute Lymphoblastic Leukemia Resulting in Synergistic in Vitro and in Vivo Interactions with Established Drugs

(2009) L. M. High et al.   MOLECULAR PHARMACOLOGY

Regulation of antiapoptotic MCL-1 function by gossypol: Mechanistic insights from in vitro reconstituted systems

(2008) Aitor Etxebarria et al.   BIOCHEMICAL PHARMACOLOGY

Gossypol, a BH3 mimetic, induces apoptosis in chronic lymphocytic leukemia cells

(2008) K. Balakrishnan et al.   BLOOD

Phase I study of obatoclax mesylate (GX15-070), a small molecule pan-Bcl-2 family antagonist, in patients with advanced chronic lymphocytic leukemia

(2008) S. M. O'Brien et al.   BLOOD

Phase II multicenter study of oblimersen sodium, a Bcl-2 antisense oligonucleotide, in combination with rituximab in patients with recurrent B-cell non-Hodgkin lymphoma

(2008) Barbara Pro et al.   BRITISH JOURNAL OF HAEMATOLOGY

Mechanisms of Antileukemic Activity of the Novel Bcl-2 Homology Domain-3 Mimetic GX15-070 (Obatoclax)

(2008) M. Konopleva et al.   CANCER RESEARCH

ABT-263: A Potent and Orally Bioavailable Bcl-2 Family Inhibitor

(2008) C. Tse et al.   CANCER RESEARCH

A Phase I Study of the Pan Bcl-2 Family Inhibitor Obatoclax Mesylate in Patients with Advanced Hematologic Malignancies

(2008) A. D. Schimmer et al.   CLINICAL CANCER RESEARCH

R-(-)−gossypol (AT-101) activates programmed cell death in multiple myeloma cells

(2008) Michael P. Kline et al.   EXPERIMENTAL HEMATOLOGY

Loss of the BH3-only protein Bmf impairs B cell homeostasis and accelerates γ irradiation–induced thymic lymphoma development

(2008) Verena Labi et al.   JOURNAL OF EXPERIMENTAL MEDICINE

BCL-2 phosphorylation modulates sensitivity to the BH3 mimetic GX15-070 (Obatoclax) and reduces its synergistic interaction with bortezomib in chronic lymphocytic leukemia cells

(2008) P Pérez-Galán et al.   LEUKEMIA

Preclinical studies of Apogossypolone: a new nonpeptidic pan small-molecule inhibitor of Bcl-2, Bcl-XL and Mcl-1 proteins in Follicular Small Cleaved Cell Lymphoma model

(2008) Alan A Arnold et al.   Molecular Cancer

In vivo efficacy of the Bcl-2 antagonist ABT-737 against aggressive Myc-driven lymphomas

(2008) K. D. Mason et al.   PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

BH3-only protein Puma contributes to death of antigen-specific T cells during shutdown of an immune response to acute viral infection

(2008) S. F. Fischer et al.   PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA