abt-199 and Neoplasms

Apoptosis is the major mode of programmed cell death, which conduces to maintain tissue homeostasis, clearance of abnormal cells and development of organisms. Over the past two decades, great progress and significant clinical benefits in cancer treatment have been made by targeting Bcl-2 anti-apoptotic proteins. However, with the deep research of clinic, the therapeutic value of single target inhibitors is restricted due to the limited monotherapy activity, potential and complex drug resistance as well as monotherapy safety. This review focuses on recent advance in discovery of novel apoptosis inducers targeting Bcl-2 anti-apoptotic proteins aiming to overcome existing therapeutic limitations, and introduce the strategies and advanced technologies in the drug design and optimization.

Topics: Antineoplastic Agents; Apoptosis; Apoptosis Regulatory Proteins; Drug Design; Neoplasms; Proto-Oncogene Proteins c-bcl-2

The removal of cells by apoptosis is an essential process regulating tissue homeostasis. Cancer cells acquire the ability to circumvent apoptosis and survive in an unphysiological tissue context. Thereby, the Bcl-2 protein family plays a key role in the initiation of apoptosis, and overexpression of the anti-apoptotic Bcl-2 proteins is one of the molecular mechanisms protecting cancer cells from apoptosis. Recently, small molecules targeting the anti-apoptotic Bcl-2 family proteins have been identified, and with venetoclax the first of these BH3 mimetics has been approved for the treatment of leukemia. In solid tumors the anti-apoptotic Bcl-2 family proteins Mcl-1 and Bcl-xL are frequently overexpressed or genetically amplified. In this review, we summarize the role of Mcl-1 and Bcl-xL in solid tumors and compare the different BH3 mimetics targeting Mcl-1 or Bcl-xL.

Topics: bcl-X Protein; Bridged Bicyclo Compounds, Heterocyclic; Gene Amplification; Gene Expression Regulation, Neoplastic; Humans; Molecular Mimicry; Myeloid Cell Leukemia Sequence 1 Protein; Neoplasms; Protein Domains; Small Molecule Libraries; Sulfonamides; Up-Regulation

B-Cell Lymphoma 2 (BCL-2), c-MYC and related proteins are arguably amongst the most widely studied in all of biology. Every year there are thousands of papers reporting on different aspects of their biochemistry, cellular and physiological mechanisms and functions. This plethora of literature can be attributed to both proteins playing essential roles in the normal functioning of a cell, and by extension a whole organism, but also due to their central role in disease, most notably, cancer. Many cancers arise due to genetic lesions resulting in deregulation of both proteins, and indeed the development and survival of tumours is often dependent on co-operativity between these protein families. In this review we will discuss the individual roles of both proteins in cancer, describe cancers where co-operativity between them has been well-characterised and finally, some strategies to target these proteins therapeutically.

Topics: Aniline Compounds; Antineoplastic Agents; Apoptosis; Biphenyl Compounds; Bridged Bicyclo Compounds, Heterocyclic; Carcinogenesis; Cell Line, Tumor; Cell Survival; Clinical Trials as Topic; Gene Expression Regulation, Neoplastic; Humans; Morpholinos; Neoplasms; Nitrophenols; Peptide Fragments; Piperazines; Proto-Oncogene Proteins c-bcl-2; Proto-Oncogene Proteins c-myc; Rituximab; Signal Transduction; Sulfonamides

The BH-3 mimetic venetoclax overcomes apoptosis and therapy resistance caused by high expression of BCL2 or loss of BH3-only protein function. Although a promising therapy for hematologic malignancies, increased expression of anti-apoptotic MCL-1 or BCL-XL, as well as other resistance mechanisms prevent a durable response to venetoclax. Recent studies demonstrate that agents targeting epigenetic mechanisms such as DNA methyltransferase inhibitors, histone deacetylase (HDAC) inhibitors, histone methyltransferase EZH2 inhibitors, or bromodomain reader protein inhibitors may disable oncogenic gene expression signatures responsible for venetoclax resistance. Combination therapies including venetoclax and epigenetic therapies are effective in preclinical models and the subject of many current clinical trials. Here we review epigenetic strategies to overcome venetoclax resistance mechanisms in hematologic malignancies.

Topics: Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Drug Resistance, Neoplasm; Enzyme Inhibitors; Epigenesis, Genetic; Humans; Neoplasms; Sulfonamides

Proteins of the Bcl-2 family are known as regulators of apoptosis, one of the most studied forms of programmed cell death. The Bcl-2 protein family is represented by both pro- and antiapoptotic members. Antiapoptotic proteins are often exploited by tumor cells to avoid their death, thus playing an important role in carcinogenesis and in acquisition of resistance to various therapeutic agents. Therefore, antiapoptotic proteins represent attractive targets for cancer therapy. A detailed investigation of interactions between Bcl-2 family proteins resulted in the development of highly selective inhibitors of individual antiapoptotic members. These agents are currently being actively studied at the preclinical and clinical stages and represent a promising therapeutic strategy, which is highlighted by approval of venetoclax, a selective inhibitor of Bcl-2, for medical use. Meanwhile, inhibition of antiapoptotic Bcl-2 family proteins has significant therapeutic potential that is yet to be revealed. In the coming era of precision medicine, a detailed study of the mechanisms responsible for the sensitivity or resistance of tumor cells to various therapeutic agents, as well as the search for the most effective combinations, is of great importance. Here, we discuss mechanisms of how the Bcl-2 family proteins function, principles of their inhibition by small molecules, success of this approach in cancer therapy, and, eventually, biochemical features that can be exploited to improve the use of Bcl-2 family inhibitors as anticancer drugs.

Topics: Animals; Antineoplastic Agents; Apoptosis; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Humans; Mice; Mitochondria; Neoplasms; Peptide Fragments; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Sulfonamides

A balance of Bcl-2 family proteins dictates cell survival or death, as the interactions between these proteins regulate mitochondrial apoptotic signaling pathways. However, cancer cells frequently show upregulation of pro-survival Bcl-2 proteins and sequester activated pro-apoptotic BH3-only proteins driven by diverse cytotoxic stresses, resulting in tumor progression and chemoresistance. Synthetic molecules from either structure-based design or screening procedures to engage and inactivate pro-survival Bcl-2 proteins and restore apoptotic process represent a chemical biological means of selectively killing malignant cells. 17 years ago, one of us reviewed on the discovery of novel Bcl-2 targeted agents [1]. Here we revisit this area and examine the progress and current status of small molecule Bcl-2 inhibitor development, demonstrating the Bcl-2 family as a valid target for cancer therapy and providing successful examples for the discovery of inhibitors that target protein-protein interactions.

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Drug Design; Humans; Neoplasms; Proto-Oncogene Proteins c-bcl-2

Apoptosis is a highly conserved programme for removing damaged and unwanted cells. Apoptosis in most cells is coordinated on mitochondria by the Bcl-2 family of proteins. The balance between pro- and anti-apoptotic Bcl-2 family proteins sets a threshold for mitochondrial apoptosis, a balance that is altered during cancer progression. Consequently, avoidance of cell death is an established cancer hallmark. Although there is a general perception that tumour cells are more resistant to apoptosis than their normal counterparts, the realities of cell death regulation in cancer are more nuanced. In this review we discuss how a profound understanding of this control has led to new therapeutic approaches, including the new class of BH3-mimetics, which directly target apoptosis as a vulnerability in cancer. We discuss recent findings that highlight the current limitations in our understanding of apoptosis and how these novel therapeutics work.

Topics: Aniline Compounds; Antineoplastic Agents; Apoptosis; Apoptosis Regulatory Proteins; Bridged Bicyclo Compounds, Heterocyclic; Humans; Mitochondria; Mitochondrial Membrane Transport Proteins; Neoplasms; Proto-Oncogene Proteins c-bcl-2; Pyrimidines; Sulfonamides; Thiophenes

Impaired apoptosis plays a central role in cancer development and limits the efficacy of conventional cytotoxic therapies. Deepening understanding of how opposing factions of the BCL-2 protein family switch on apoptosis and of their structures has driven development of a new class of cancer drugs that targets various pro-survival members by mimicking their natural inhibitors, the BH3-only proteins. These 'BH3 mimetic' drugs seem destined to become powerful new weapons in the arsenal against cancer. Successful clinical trials of venetoclax/ABT-199, a specific inhibitor of BCL-2, have led to its approval for a refractory form of chronic lymphocytic leukaemia and to scores of on-going trials for other malignancies. Furthermore, encouraging preclinical studies of BH3 mimetics that target other BCL-2 pro-survival members, particularly MCL-1, offer promise for cancers resistant to venetoclax. This review sketches the impact of the BCL-2 family on cancer development and therapy, describes how interactions of family members trigger apoptosis and discusses the potential of BH3 mimetic drugs to advance cancer therapy.

Topics: Animals; Antineoplastic Agents; Apoptosis; Apoptosis Regulatory Proteins; Bridged Bicyclo Compounds, Heterocyclic; Humans; Mitochondrial Membranes; Neoplasms; Proto-Oncogene Proteins c-bcl-2; Sulfonamides

A hallmark of cancer is the evasion of apoptosis, which is often associated with the upregulation of the antiapoptotic members of the Bcl-2 family of proteins. The prosurvival function of the antiapoptotic Bcl-2 proteins is manifested by capturing and neutralizing the proapoptotic Bcl-2 proteins via their BH3 death domains. Accordingly, strategies to antagonize the antiapoptotic Bcl-2 proteins have largely focused on the development of low-molecular-weight, synthetic BH3 mimetics ("magic bullets") to disrupt the protein-protein interactions between anti- and proapoptotic Bcl-2 proteins. In this way, apoptosis has been reactivated in malignant cells. Moreover, several such Bcl-2 family inhibitors are presently being evaluated for a range of cancers in clinical trials and show great promise as new additions to the cancer armamentarium. Indeed, the selective Bcl-2 inhibitor venetoclax (Venclexta) recently received FDA approval for the treatment of a specific subset of patients with chronic lymphocytic leukemia. This review focuses on the major developments in the field of Bcl-2 inhibitors over the past decade, with particular emphasis on binding modes and, thus, the origins of selectivity for specific Bcl-2 family members.

Topics: Apoptosis; Humans; Neoplasms; Proto-Oncogene Proteins c-bcl-2; Small Molecule Libraries

Topics: Aniline Compounds; Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Apoptosis Regulatory Proteins; Bridged Bicyclo Compounds, Heterocyclic; Drug Screening Assays, Antitumor; Humans; Indoles; MAP Kinase Signaling System; Mitochondrial Dynamics; Molecular Targeted Therapy; Neoplasm Proteins; Neoplasms; Oncogene Addiction; Proto-Oncogene Proteins c-bcl-2; Pyrroles; Sulfonamides

The intracellular protein B-cell-lymphoma-2 (BCL2) has been considered an attractive target for cancer therapy since the discovery of its function as a major promoter of cell survival (an anti-apoptotic) in the late 1980s. However, the challenges of targeting a protein-protein interaction delayed the discovery of fit-for-purpose molecules until the mid-2000s. Since then, a series of high affinity small organic molecules that inhibits the interaction of BCL2 with the apoptotic machinery, the so-called BH3-mimetics, have been developed. Venetoclax (formerly ABT-199) is the first to achieve US Food and Drug Administration approval, with an indication for treatment of patients with previously treated chronic lymphocytic leukemia (CLL) bearing deletion of the long arm of chromosome 17. Here, we review key aspects of the science underpinning the clinical application of BCL2 inhibitors and explore both our current knowledge and unresolved questions about its clinical utility, both in CLL and in other B-cell malignancies that highly express BCL2.

Topics: Animals; Antineoplastic Agents; Apoptosis; Bridged Bicyclo Compounds, Heterocyclic; Drug Approval; Drug Design; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Neoplasms; Proto-Oncogene Proteins c-bcl-2; Sulfonamides

The approval of venetoclax, a 'BH3-mimetic' antagonist of the BCL-2 anti-apoptotic protein, for chronic lymphocytic leukemia represents a major milestone in translational apoptosis research. Venetoclax has already received 'breakthrough' designation for acute myeloid leukemia, and is being studied in many other tumor types. However, resistance to BCL-2 inhibitor monotherapy may rapidly ensue. Several studies have shown that the other two major anti-apoptotic BCL-2 family proteins, BCL-X

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; bcl-X Protein; Biomimetics; Bridged Bicyclo Compounds, Heterocyclic; Clinical Trials as Topic; Drug Discovery; Drug Resistance, Neoplasm; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Myeloid Cell Leukemia Sequence 1 Protein; Neoplasms; Peptide Fragments; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Sulfonamides

BCL-2 proteins are key players in the balance of cell life and death. Their roles in the development and biology of cancer have been well established and continue to be investigated. Understanding the mechanisms by which these proteins regulate apoptosis has led to the development of small molecule targeted therapies that act to overcome the cell's ability to evade programmed cell death. Areas covered: The biology of the intrinsic apoptotic pathway is reviewed with attention to the varied roles of the anti-apoptotic members of the BCL-2 family. BH3 profiling is reviewed. Historical therapeutic agents are addressed, and currently investigated BH3 mimetics are described with attention to clinical significance. The limitations of BCL-2 family targeted drugs with regard to on-target and off-target toxicities are explored. Agents under development for targeting MCL-1 and other BCL-2 family members are discussed. Expert opinion: ABT-199 (venetoclax) and other BH3 mimetics have entered the clinical arena and show promising results in both hematologic and solid malignancies. Use of agents targeting this system will likely expand, and likely a number of malignant diseases will be successfully targeted resulting in improved treatment responses and patient survival.

Topics: Animals; Antineoplastic Agents; Apoptosis; Bridged Bicyclo Compounds, Heterocyclic; Drug Design; Humans; Molecular Targeted Therapy; Neoplasms; Proto-Oncogene Proteins c-bcl-2; Sulfonamides; Survival Rate

In 1988, the BCL-2 protein was found to promote cancer by limiting cell death rather than enhancing proliferation. This discovery set the wheels in motion for an almost 30 year journey involving many international research teams that has recently culminated in the approval for a drug, ABT-199/venetoclax/Venclexta that targets this protein in the treatment of cancer. This review will describe the long and winding path from the discovery of this protein and understanding the fundamental process of apoptosis that BCL-2 and its numerous homologues control, through to its exploitation as a drug target that is set to have significant benefit for cancer patients.

Topics: Aniline Compounds; Animals; Antineoplastic Agents; Apoptosis; Bridged Bicyclo Compounds, Heterocyclic; Drug Design; Drug Discovery; Genes, bcl-2; Humans; Neoplasms; Protein Interaction Maps; Proto-Oncogene Proteins c-bcl-2; Sulfonamides

Mutations that impair apoptosis contribute to cancer development and reduce the effectiveness of conventional anti-cancer therapies. These insights and understanding of how the B cell lymphoma (BCL)-2 protein family governs apoptosis have galvanized the search for a new class of cancer drugs that target its pro-survival members by mimicking their natural antagonists, the BCL-2 homology (BH)3-only proteins. Successful initial clinical trials of the BH3 mimetic venetoclax/ABT-199, specific for BCL-2, have led to its recent licensing for refractory chronic lymphocytic leukemia and to multiple ongoing trials for other malignancies. Moreover, preclinical studies herald the potential of emerging BH3 mimetics targeting other BCL-2 pro-survival members, particularly myeloid cell leukemia (MCL)-1, for multiple cancer types. Thus, BH3 mimetics seem destined to become powerful new weapons in the arsenal against cancer. This review sketches the discovery of the BCL-2 family and its impact on cancer development and therapy; describes how interactions of family members trigger apoptosis; outlines the development of BH3 mimetic drugs; and discusses their potential to advance cancer therapy.

Topics: Aniline Compounds; Animals; Antineoplastic Agents; Apoptosis; Bridged Bicyclo Compounds, Heterocyclic; Humans; Neoplasms; Proto-Oncogene Proteins c-bcl-2; Sulfonamides

Malignant cells routinely violate cellular checkpoints that should initiate cell death in normal cells by triggering pro-apoptotic members of the BCL-2 family of proteins. To escape such death inducing signals, cancer cells often select for upregulation of anti-apoptotic BCL-2 family members including BCL-2, BCL-XL , BFL-1, BCL-W and MCL-1. These family members prevent death by sequestering pro-apoptotic molecules. To counter this resistance mechanism, small molecule inhibitors of anti-apoptotic BCL-2 family members have been under development. These molecules have shown promise in pre-clinical and clinical testing to overcome apoptotic resistance, prompting cancer cells to undergo apoptosis. Alternatively, other strategies have taken advantage of the normal regulatory machinery controlling anti-apoptotic molecules and have used inhibitors of signaling pathways to down-modulate the expression of anti-apoptotic molecules, thus tilting the balance in cancer cells to cell death. This review explores recent developments and strategies aimed at antagonizing anti-apoptotic BCL-2 family member action to promote the induction of cell death in cancer therapy.

Topics: Aniline Compounds; Animals; Antineoplastic Agents; Apoptosis; bcl-2-Associated X Protein; Bridged Bicyclo Compounds, Heterocyclic; Drug Design; Humans; Inhibitor of Apoptosis Proteins; Models, Biological; Myeloid Cell Leukemia Sequence 1 Protein; Neoplasms; Proto-Oncogene Proteins c-bcl-2; Signal Transduction; Sulfonamides

Targeting apoptosis is an attractive approach in cancer therapy. The BH3-only proteins of the BCL-2 family (having only the BCL-2 homology domain BH3) can trigger apoptosis by binding to the prosurvival members of this family and neutralizing their functional activity (sequestration of the proapoptotic Bcl-2 family members). The "BH3 mimetic" concept has prompted the development of small molecules capable of mimicking BH3-only proteins and thus inducing apoptosis. The prototype BH3 mimetic ABT-737 selectively targets the three prosurvival proteins BCL-XL, BCL-2, and BCL-W (but not MCL-1 or A1) and its oral derivative ABT-263 has proved promising in clinical trials. Some putative BH3 mimetics are also tested clinically while others are still being characterized. This article recapitulates the various known BH3 mimetics and presents the recent developments in the field. The latter include (i) the identification of molecular determinants responsible for the specific interactions between BH3 motifs and the binding grooves of prosurvival proteins and (ii) the characterization of new compounds and particularly BH3 mimetics that antagonize either selectively MCL-1 or BCL-2 or a broad range of prosurvival proteins. These data are critical advances toward the discovery of novel anticancer agents.

Topics: Amino Acid Motifs; Aniline Compounds; Antineoplastic Agents; Apoptosis; Bridged Bicyclo Compounds, Heterocyclic; Clinical Trials as Topic; Drug Design; Drug Screening Assays, Antitumor; Gossypol; Humans; Indoles; Molecular Mimicry; Neoplasms; Peptide Fragments; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Pyrroles; Sulfonamides

Venetoclax is a highly selective, potent BCL-2 inhibitor that is approved for some patients previously treated for chronic lymphocytic leukemia, and has shown promising activity in adult studies across several hematologic malignancies. Preclinical studies have demonstrated venetoclax activity in pediatric patient-derived xenograft models and cell lines; however, clinical studies in pediatric patients have yet to be conducted. The prognosis is poor for children with most relapsed/refractory malignancies, and limited treatment options result in unmet clinical need. Herein, we describe the rationale and design of the first study of venetoclax in pediatric patients with relapsed/refractory malignancies: a Phase I trial investigating the safety and pharmacokinetics of venetoclax monotherapy followed by the addition of chemotherapy (Trial registration: EudraCT 2017-000439-14; NCT03236857).

Topics: Age Factors; Antineoplastic Agents; Biomarkers; Bridged Bicyclo Compounds, Heterocyclic; Child, Preschool; Clinical Protocols; Drug Development; Drug Resistance, Neoplasm; Humans; Neoplasms; Recurrence; Research Design; Sulfonamides; Treatment Outcome

Cancer cells are resistant to apoptosis and this is one of the most obvious symptoms of cancer in humans. One of the most exciting strategies for treating cancer is to design regulators that increase cell death and stop cell growth. Members of the BCL-2 family of proteins play an important role in the regulation of apoptosis. In this study, an attempt was made to improve the performance of one of the anticancer drugs by designing new analogs of venetoclax (VNT). For this purpose, molecular docking studies were performed to determine the best binding state of VNT and its newly designed derivatives at the protein-binding site to estimate the binding energy. The best analog in terms of free energy was VNT-12 with the lowest energy (-12.15 kcal/mol). Finally, to investigate the inhibitory effect of the compounds on BCL-2 protein, molecular dynamics simulation was used, and by performing the relevant analyses during the simulation, it was observed that the newly designed ligand had better performance in inhibiting BCL-2 protein compared to VNT.

Topics: Antineoplastic Agents; Apoptosis; Bridged Bicyclo Compounds, Heterocyclic; Humans; Molecular Docking Simulation; Neoplasms; Proto-Oncogene Proteins c-bcl-2

Topics: Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Humans; Leukemia, Myeloid, Acute; Myeloproliferative Disorders; Neoplasms; Sulfonamides

We developed a phenotypic screening platform for the functional exploration of dendritic cells (DC). Here, we report a genome-wide CRISPR screen that revealed BCL2 as an endogenous inhibitor of DC function. Knockout of BCL2 enhanced DC antigen presentation and activation as well as the capacity of DCs to control tumors and to synergize with PD-1 blockade. The pharmacologic BCL2 inhibitors venetoclax and navitoclax phenocopied these effects and caused a cDC1-dependent regression of orthotopic lung cancers and fibrosarcomas. Thus, solid tumors failed to respond to BCL2 inhibition in mice constitutively devoid of cDC1, and this was reversed by the infusion of DCs. Moreover, cDC1 depletion reduced the therapeutic efficacy of BCL2 inhibitors alone or in combination with PD-1 blockade and treatment with venetoclax caused cDC1 activation, both in mice and in patients. In conclusion, genetic and pharmacologic BCL2 inhibition unveils a DC-specific immune checkpoint that restrains tumor immunosurveillance.. BCL2 inhibition improves the capacity of DCs to stimulate anticancer immunity and restrain cancer growth in an immunocompetent context but not in mice lacking cDC1 or mature T cells. This study indicates that BCL2 blockade can be used to sensitize solid cancers to PD-1/PD-L1-targeting immunotherapy. This article is featured in Selected Articles from This Issue, p. 2293.

Topics: Animals; Antineoplastic Agents; Dendritic Cells; Humans; Mice; Mice, Knockout; Monitoring, Immunologic; Neoplasms; Programmed Cell Death 1 Receptor; Proto-Oncogene Proteins c-bcl-2

Topics: Aged; Busulfan; Decitabine; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Myeloproliferative Disorders; Neoplasms; Prospective Studies; Recurrence; Transplantation Conditioning

Induction of apoptosis by the FDA-approved drug Venetoclax in cancer cells mainly derives from blocking the interactions between BCL-2 and BH3-only proteins. Anti-apoptotic BFL-1, a homolog of BCL-2, also competitively binds to the BH3-only proteins and is responsible for Venetoclax-induced drug resistance. Compared to BCL-2, small-molecule inhibitors of BFL-1 are relatively underexplored. In order to tackle this issue, in-house compound library was screened and a hit compound was identified and optimized to obtain 12 (ZH97) functioning as a covalent and selective inhibitor of BFL-1. 12 modifies BFL-1 at the C55 residue, blocks BFL-1/BID interaction in vitro, promotes cellular cytochrome c release from mitochondria, and induced apoptosis in BFL-1 overexpressing cancer cells. Mechanistic studies show that 12 inhibited BFL-1/PUMA interaction in cell lysate and is effective in cancer cells that harboring high expression level of BFL-1. In summary, blockade of BFL-1/BH3-only proteins interactions with a covalent small-molecule inhibitor induced apoptosis and elicited antitumor activity. Thus, our study demonstrates an appealing strategy for selective modulation of cellular BFL-1 for cancer therapy.

Topics: Apoptosis; Methylcellulose; Minor Histocompatibility Antigens; Mitochondria; Neoplasms; Proto-Oncogene Proteins c-bcl-2

Venetoclax has transformed the treatment landscape in hematologic malignancies, especially in elderly population. With high rates of remission, deep and durable responses, and safe toxicity profile, venetoclax in combination therapy has been extremely effective, garnering accelerated approval and becoming standard of care in lymphoid and myeloid malignancies.. Preclinical and clinical experience of venetoclax monotherapy and combination therapy in relapsed/refractory and frontline CLL, AML, ALL, high-risk MDS and BPDCN with an emphasis on key clinical trials and efficacy of combination regimens in distinct mutational landscapes. Strategies to mitigate myelosuppression and manage dose adjustments and infectious complications are addressed.. Targeting BCL-2 offers a safe and highly effective adjunct to available therapies in hematologic malignancies. Despite success and frequent utilization of venetoclax, several resistance mechanisms have been elucidated, prompting the development of novel combinatorial strategies. Further, on-target myelosuppression of venetoclax is a key obstacle in clinical practice, requiring diligent monitoring and practice-based knowledge of dose modifications. Despite these limitations, venetoclax has gained tremendous popularity in hematologic-oncology, becoming an integral component of numerous combination regimes, with ongoing plethora of clinical trials encompassing standard chemotherapy, targeted agents and immune-based approaches.

Topics: Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Humans; Neoplasms; Sulfonamides

Aberrantly activated Hedgehog (Hh) pathway is critical for driving the initiation and progression of multiple types of cancers, including medulloblastoma (MB) and basal cellular carcinoma (BCC). The majority of current Hh antagonist function by targeting the transmembrane domain of the oncoprotein Smoothened (Smo), a G-protein-coupled receptor-like receptor of Hh pathway. However, the primary and acquired resistance to current Smo inhibitors raise a critical need to develop next-generation of Smo inhibitors to improve their clinical efficacy. In this study, we identify that FDA approved drug ABT-199 significantly and selectively inhibits the Hh pathway. Mechanistically, ABT-199 acts as a competitive inhibitor of oxysterol by potentially targeting the cysteine rich domain (CRD) of Smo, rather as a BH3 mimetic. ABT-199 obviously inhibits the growth of Hh-driven tumors and possesses capacity of combating the primary and acquired resistance to Smo inhibitors caused by Smo mutations. Our data reposition ABT-199 as a Smo inhibitor for treating Hh-driven tumors, especially for those bearing Smo mutations and resistant to current Smo inhibitors. Meanwhile, our findings strengthen the argument that the CRD of Smo is a promising target for developing novel Smo inhibitors with capacity of combating the resistance to Smo inhibitors.

Topics: Animals; Antineoplastic Agents; Binding Sites; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Drug Resistance, Neoplasm; Hedgehog Proteins; Humans; Hydroxycholesterols; Male; Mice; Mice, Inbred NOD; Mice, SCID; Neoplasms; NIH 3T3 Cells; Protein Binding; Signal Transduction; Smoothened Receptor; Sulfonamides

Apoptosis, a form of programmed cell death, is a highly regulated process critical for tissue development, homeostasis, and pathogenesis of various diseases [...].

Topics: Animals; Antineoplastic Agents; Apoptosis; Bridged Bicyclo Compounds, Heterocyclic; Gene Expression Regulation, Neoplastic; Humans; Mitochondria; Mitochondrial Membranes; Neoplasms; Proto-Oncogene Proteins c-bcl-2; Signal Transduction; Sulfonamides

Translation is a highly regulated process that is perturbed in human cancers, often through activation of the PI3K/mTOR pathway which impacts directly on the ribosome recruitment phase of translation initiation. While significant research has focused on "drugging" components of the PI3K/mTOR network, efforts have also been directed towards inhibiting eukaryotic initiation factor (eIF) 4F-dependent translation. Small molecule inhibitors of this complex have been identified, characterized, and used to validate the rationale of targeting this step to curtail tumor cell growth and modulate chemotherapy response. One such class of compounds are the rocaglates, secondary metabolites from the plant genus Aglaia, which target the RNA helicase subunit of eIF4F, eIF4A. Here we explore the ability of synthetic derivatives of aglaiastatins and an aglaroxin derivative to target the translation process in vitro and in vivo and find the synthetic derivative oxo-aglaiastatin to possess such activity. Oxo-aglaiastatin inhibited translation in vitro and in vivo and synergized with doxorubicin, ABT-199 (a Bcl-2 antagonist), and dexamethasone when tested on hematological cancer cells. The biological activity of oxo-aglaiastatin was shown to be a consequence of inhibiting eIF4A1 activity.

Topics: Aglaia; Animals; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Doxorubicin; Drug Synergism; Eukaryotic Initiation Factor-4A; Female; Humans; Lymphoma; Mice, Inbred C57BL; Neoplasms; Peptide Chain Initiation, Translational; Sulfonamides

Topics: Antineoplastic Combined Chemotherapy Protocols; Bridged Bicyclo Compounds, Heterocyclic; Decitabine; Humans; Leukemia, Myeloid, Acute; Neoplasms; Neoplasms, Second Primary; Sulfonamides; Treatment Outcome

Upregulation of antiapoptotic Bcl-2 proteins in certain tumors confers cancer cell resistance to chemotherapy or radiations. Members of the antiapoptotic Bcl-2 proteins, including Bcl-2, Mcl-1, Bcl-xL, Bcl-w, and Bfl-1, inhibit apoptosis by selectively binding to conserved α-helical regions, named BH3 domains, of pro-apoptotic proteins such as Bim, tBid, Bad, or NOXA. Five antiapoptotic proteins have been identified that interact with various selectivity with BH3 containing pro-apoptotic counterparts. Cancer cells present various and variable levels of these proteins, making the design of effective apoptosis based therapeutics challenging. Recently, BH3 profiling was introduced as a method to classify cancer cells based on their ability to resist apoptosis following exposure to selected BH3 peptides. However, these studies were based on binding affinities measured with model BH3 peptides and Bcl-2-proteins taken from mouse sequences. While the majority of these interactions are conserved between mice and humans, we found surprisingly that human NOXA binds to human Bfl-1 potently and covalently via conserved Cys residues, with over 2 orders of magnitude increased affinity over hMcl-1. Our data suggest that some assumptions of the original BH3 profiling need to be revisited and that perhaps further targeting efforts should be redirected toward Bfl-1, for which no suitable specific inhibitors or pharmacological tools have been reported. In this regard, we also describe the initial design and characterizations of novel covalent BH3-based agents that potently target Bfl-1. These molecules could provide a novel platform on which to design effective Bfl-1 targeting therapeutics.

Topics: Amino Acid Sequence; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Drug Resistance, Neoplasm; Humans; Minor Histocompatibility Antigens; Neoplasms; Proto-Oncogene Proteins c-bcl-2

Topics: Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Cell Proliferation; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Neoplasms; Proto-Oncogene Proteins c-bcl-2; Sulfonamides

Topics: Animals; Antineoplastic Agents; Apoptosis; Bridged Bicyclo Compounds, Heterocyclic; Drug Approval; Humans; Neoplasms; Proto-Oncogene Proteins c-bcl-2; Sulfonamides; United States

Anti-apoptotic BCL-2 family members antagonise apoptosis by sequestering their pro-apoptotic counterparts. The balance between the different BCL-2 family members forms the basis of BH3 profiling, a peptide-based technique used to predict chemosensitivity of cancer cells. Recent identification of cell-permeable, selective inhibitors of BCL-2, BCL-XL and MCL-1, further facilitates the determination of the BCL-2 family dependency of cancer cells.. We use BH3 profiling in combination with cell death analyses using a chemical inhibitor toolkit to assess chemosensitivity of cancer cells.. Both BH3 profiling and the inhibitor toolkit effectively predict chemosensitivity of cells addicted to a single anti-apoptotic protein but a combination of both techniques is more instructive when cell survival depends on more than one anti-apoptotic protein.. The inhibitor toolkit provides a rapid, inexpensive and simple means to assess the chemosensitivity of tumour cells and in conjunction with BH3 profiling offers much potential in personalising cancer therapy.

Topics: Amino Acid Sequence; Antineoplastic Agents; Apoptosis; Benzothiazoles; Biomimetic Materials; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Humans; Isoquinolines; Molecular Sequence Data; Neoplasms; Peptide Fragments; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Sulfonamides

Topics: Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Humans; Neoplasms; Proto-Oncogene Proteins c-bcl-2; Sulfonamides

The BCL-2/BCL-XL/BCL-W inhibitor ABT-263 (navitoclax) has shown promising clinical activity in lymphoid malignancies such as chronic lymphocytic leukemia. However, its efficacy in these settings is limited by thrombocytopenia caused by BCL-XL inhibition. This prompted the generation of the BCL-2-selective inhibitor venetoclax (ABT-199/GDC-0199), which demonstrates robust activity in these cancers but spares platelets. Navitoclax has also been shown to enhance the efficacy of docetaxel in preclinical models of solid tumors, but clinical use of this combination has been limited by neutropenia. We used venetoclax and the BCL-XL-selective inhibitors A-1155463 and A-1331852 to assess the relative contributions of inhibiting BCL-2 or BCL-XL to the efficacy and toxicity of the navitoclax-docetaxel combination. Selective BCL-2 inhibition suppressed granulopoiesis in vitro and in vivo, potentially accounting for the exacerbated neutropenia observed when navitoclax was combined with docetaxel clinically. By contrast, selectively inhibiting BCL-XL did not suppress granulopoiesis but was highly efficacious in combination with docetaxel when tested against a range of solid tumors. Therefore, BCL-XL-selective inhibitors have the potential to enhance the efficacy of docetaxel in solid tumors and avoid the exacerbation of neutropenia observed with navitoclax. These studies demonstrate the translational utility of this toolkit of selective BCL-2 family inhibitors and highlight their potential as improved cancer therapeutics.

Topics: Administration, Oral; Aniline Compounds; Animals; Antineoplastic Agents; bcl-X Protein; Benzothiazoles; Bridged Bicyclo Compounds, Heterocyclic; Cell Line, Tumor; Cell Survival; Docetaxel; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Granulocytes; Humans; Isoquinolines; Kinetics; Mice; Neoplasm Transplantation; Neoplasms; Neutropenia; Neutrophils; Proto-Oncogene Proteins c-bcl-2; Sulfonamides; Taxoids; Thrombocytopenia