B-cell Lymphoma 6 Inhibitors: Current Advances and Prospects of Drug Development for Diffuse Large B-cell Lymphomas

Gu, Haijun; He, Jiaxun; Li, Yuzhan; Mi, Dazhao; Guan, Tian; Guo, Weikai; Liu, Bo; Chen, Yi Hua

doi:10.1021/acs.jmedchem.2c01433

Cited by 12 publications

(5 citation statements)

References 138 publications

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“…Mammalian BTB-C2H2 proteins, including Kaiso, are important transcriptional regulators involved in organismal development and cell differentiation [32,33,80,81]. Impaired expression of BTB-C2H2 proteins is closely correlated with tumorigenesis [82][83][84][85][86][87][88][89]. Currently, anticancer inhibitors are being actively developed that bind to individual regions of the BTB domain and block interactions with partner proteins [90][91][92][93][94][95][96][97].…”

Section: Discussionmentioning

confidence: 99%

The N-Terminal Part of Drosophila CP190 Is a Platform for Interaction with Multiple Architectural Proteins

Golovnin,

Melnikova,

Babosha

et al. 2023

IJMS

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CP190 is a co-factor in many Drosophila architectural proteins, being involved in the formation of active promoters and insulators. CP190 contains the N-terminal BTB/POZ (Broad-Complex, Tramtrack and Bric a brac/POxvirus and Zinc finger) domain and adjacent conserved regions involved in protein interactions. Here, we examined the functional roles of these domains of CP190 in vivo. The best-characterized architectural proteins with insulator functions, Pita, Su(Hw), and dCTCF, interacted predominantly with the BTB domain of CP190. Due to the difficulty of mutating the BTB domain, we obtained a transgenic line expressing a chimeric CP190 with the BTB domain of the human protein Kaiso. Another group of architectural proteins, M1BP, Opbp, and ZIPIC, interacted with one or both of the highly conserved regions in the N-terminal part of CP190. Transgenic lines of D. melanogaster expressing CP190 mutants with a deletion of each of these domains were obtained. The results showed that these mutant proteins only partially compensated for the functions of CP190, weakly binding to selective chromatin sites. Further analysis confirmed the essential role of these domains in recruitment to regulatory regions associated with architectural proteins. We also found that the N-terminal of CP190 was sufficient for recruiting Z4 and Chromator proteins and successfully achieving chromatin opening. Taken together, our results and the results of previous studies showed that the N-terminal region of CP190 is a platform for simultaneous interaction with various DNA-binding architectural proteins and transcription complexes.

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Section: Discussionmentioning

confidence: 99%

The N-Terminal Part of Drosophila CP190 Is a Platform for Interaction with Multiple Architectural Proteins

Golovnin,

Melnikova,

Babosha

et al. 2023

IJMS

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“…A different type of modification relied on improving the molecular dynamics to stabilize the interaction between the inhibitor and FLT3 inactive state, driving anti-proliferative activity in vitro and in vivo [ 5 ]. In diffuse large B-cell lymphoma (DLBCL), targeting BCL6, a transcriptional repressor involved in the formation of germinal centers might be a powerful tool to treat these patients [ 6 ]. In addition, small molecules were designed to target protein abundance using small mRNA splice modulation and protein degradation rather than using the inhibitory mechanism against a specific protein [ 7 ].…”

Section: State Of the Art Of Treatment In Onco-hematological Diseasesmentioning

confidence: 99%

Is It Still Possible to Think about HSP70 as a Therapeutic Target in Onco-Hematological Diseases?

et al. 2023

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The search for molecules to be targeted that are involved in apoptosis resistance/increased survival and pathogenesis of onco-hematological malignancies is ongoing since these diseases are still not completely understood. Over the years, a good candidate has been identified in the Heat Shock Protein of 70kDa (HSP70), a molecule defined as “the most cytoprotective protein ever been described”. HSP70 is induced in response to a wide variety of physiological and environmental insults, allowing cells to survive lethal conditions. This molecular chaperone has been detected and studied in almost all the onco-hematological diseases and is also correlated to poor prognosis and resistance to therapy. In this review, we give an overview of the discoveries that have led us to consider HSP70 as a therapeutic target for mono- or combination-therapies in acute and chronic leukemias, multiple myeloma and different types of lymphomas. In this excursus, we will also consider HSP70 partners, such as its transcription factor HSF1 or its co-chaperones whose druggability could indirectly affect HSP70. Finally, we will try to answer the question asked in the title of this review considering that, despite the effort made by research in this field, HSP70 inhibitors never reached the clinic.

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“…It is prospective for the design of structurally novel as well as efficacious methuosis inducers for cancer therapy, especially for those malignancies that are still a major clinical challenge, such as TNBC. The bioactive compounds bearing pyrimidinediamine scaffold have characterized superior proliferation inhibitory activities and in vivo pharmacodynamic activity in a broad spectrum of tumors, including TNBC. − Under the circumstances, an in-house laboratory screen of approximately 100 pyrimidinediamines was conducted based on the inhibition rate of compound treatment of HCC1806 cells at the concentration of 1 μM (data not shown). The screening yielded a hit compound 2a with moderate inhibitory activity and the capability to induce cytoplasmic vacuolation (Figure S1).…”

Section: Introductionmentioning

confidence: 99%

Discovery of Pyrimidinediamine Derivatives as Potent Methuosis Inducers for the Treatment of Triple-Negative Breast Cancer

Wang

et al. 2023

J. Med. Chem.

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Triple-negative breast cancer (TNBC) is a leading malignancy among women that currently lack effective targeted therapeutic agents, and the limitations of treatment have prompted the emergence of new strategies. Methuosis is a novel vacuolepresenting cell death modality that promotes tumor cell death. Hence, a series of pyrimidinediamine derivatives were designed and synthesized through evaluation of their abilities that inhibit proliferation as well as induce methuosis against TNBC cells. Among them, JH530 showed excellent anti-proliferative activities and vacuolization capacity in TNBC. The mechanism research indicated that JH530 caused cell death through inducing methuosis of cancer cells. Furthermore, JH530 inhibited tumor growth remarkably in the HCC1806 xenograft model without an apparent decrease in body weight. Overall, JH530 is a methuosis inducer that displayed remarkable suppression of TNBC growth in vitro and in vivo, which provides a basis for the future progress of more small molecules for TNBC treatment.

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B-cell Lymphoma 6 Inhibitors: Current Advances and Prospects of Drug Development for Diffuse Large B-cell Lymphomas

Cited by 12 publications

References 138 publications

The N-Terminal Part of Drosophila CP190 Is a Platform for Interaction with Multiple Architectural Proteins

The N-Terminal Part of Drosophila CP190 Is a Platform for Interaction with Multiple Architectural Proteins

Is It Still Possible to Think about HSP70 as a Therapeutic Target in Onco-Hematological Diseases?

Discovery of Pyrimidinediamine Derivatives as Potent Methuosis Inducers for the Treatment of Triple-Negative Breast Cancer

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