Discovery of a B-Cell Lymphoma 6 Protein–Protein Interaction Inhibitor by a Biophysics-Driven Fragment-Based Approach

Kamada, Yusuke; Sakai, Nozomu; Sogabe, Satoshi; Ida, Koh; Oki, Hideyuki; Sakamoto, Kotaro; Lane, Weston; Snell, G.; Iida, Motoo; Imaeda, Yasuhiro; Sakamoto, Junichi; Matsui, Junji

doi:10.1021/acs.jmedchem.7b00313

Cited by 45 publications

(72 citation statements)

References 47 publications

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“…However, their use is limited due to the low binding affinity of most of these molecules [22][23][24]. Despite recent advances in developing BCL6 inhibitors [19,[25][26][27][28], no compound has yet reached the clinic. Furthermore, there exist controversies around the rationale and the impact of targeting BCL6 as a monotherapy due to the presence of high intra-and inter-tumor heterogeneity regarding type and number of oncogenic mutations [2,3] and the possibility of oncogene addiction switching following BCL6 targeted therapies by reactivating BCL2-family dependent anti-apoptotic pathways [29].…”

Section: Introductionmentioning

confidence: 99%

Inducible knock-out of BCL6 in lymphoma cells results in tumor stasis

et al. 2020

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Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphomas worldwide and is characterized by a high diversity of genetic and molecular alterations. Chromosomal translocations and mutations leading to deregulated expression of the transcriptional repressor BCL6 occur in a significant fraction of DLBCL patients. An oncogenic role of BCL6 in the initiation of DLBCL has been shown as the constitutive expression of BCL6 in mice recapitulates the pathogenesis of human DLBCL. However, the role of BCL6 in tumor maintenance remains poorly investigated due to the absence of suitable genetic models and limitations of pharmacological inhibitors. Here, we have utilized tetracycline-inducible CRISPR/Cas9 mutagenesis to study the consequences of BCL6 deletion in established DLBCL models in culture and in vivo. We show that BCL6 knockout in SU-DHL-4 cells in vitro results in an anti-proliferative response 4-7 days after Cas9 induction that was characterized by cell cycle (G1) arrest. Conditional BCL6 deletion in established DLBCL tumors in vivo induced a significant tumor growth inhibition with initial tumor stasis followed by slow tumor growth kinetics. Our findings support a role of BCL6 in the maintenance of lymphoma growth and showcase the utility of inducible CRISPR/ Cas9 systems for probing oncogene addiction. Recent comprehensive sequencing studies in a large cohort of DLBCL patients highlight the heterogeneity of alterations including somatic mutations, copy number alterations, and structural variants [2-4]. Among the most frequently rearranged genes are IGH, BCL2, BCL6, and MYC, with 40%, 21%, 19%, and 8% of cases affected, respectively [5-8]. BCL6 is a DNA-binding protein that represses gene transcription in Germinal Center (GC) B-cells through the recruitment of corepressor proteins. In GCs, BCL6 inhibits DNA damage response pathways and thereby prevents cell cycle arrest and apoptosis during class switch recombination and somatic hypermutation required for antibody maturation in B-cells. Subsequent BCL6 downregulation is crucial

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Section: Introductionmentioning

confidence: 99%

Inducible knock-out of BCL6 in lymphoma cells results in tumor stasis

et al. 2020

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“…Recently, a high affinity BCL6-binding peptide has been reported, 13 as well as a fragment-screen derived small molecule binder. 14 We also recently reported high affinity, selective small molecule cellular probes for BCL6 but they failed to demonstrate a significant BCL6 dependent antiproliferative effect in DLBCL cell lines. 15 Here, we present a new series of high activity, selective small molecule BCL6 inhibitors which we were also able to convert into chemical biology tools.…”

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confidence: 98%

Development of a Novel B-Cell Lymphoma 6 (BCL6) PROTAC To Provide Insight into Small Molecule Targeting of BCL6

et al. 2018

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B-cell lymphoma 6 (BCL6) inhibition is a promising mechanism for treating hematological cancers but high quality chemical probes are necessary to evaluate its therapeutic potential. Here we report potent BCL6 inhibitors that demonstrate cellular target engagement and exhibit exquisite selectivity for BCL6 based on mass spectrometry analyses following chemical proteomic pulldown. Importantly, a proteolysis-targeting chimera (PROTAC) was also developed and shown to significantly degrade BCL6 in a number of The structures of BCL6 BTB domain bound to compounds 1, 2 and 9 have been deposited in the Protein Data Bank with PDB accession codes 6ew6, 6ew7 and 6ew8, respectively. AUTHOR INFORMATIONCorresponding Author

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“… 19 BCL6 is considered as a therapeutic target for autoimmune diseases and cancer treatment. 20 We hypothesized that BCL6 would inhibit renal inflammation via negative regulation of NLRP3 transcription and would be beneficial in attenuating hypertension. The present study was designed to determine whether BCL6 attenuates renal NLRP3 inflammasome activation and inflammation and its underlying mechanism.…”

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confidence: 99%

BCL6 attenuates renal inflammation via negative regulation of NLRP3 transcription

et al. 2017

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Renal inflammation contributes to the pathogeneses of hypertension. This study was designed to determine whether B-cell lymphoma 6 (BCL6) attenuates renal NLRP3 inflammasome activation and inflammation and its underlying mechanism. Male spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) were used in the present study. Angiotensin (Ang) II or lipopolysaccharides (LPS) was used to induce inflammation in HK-2 cells, a human renal tubular epithelial (RTE) cell line. NLRP3 inflammasome was activated and BCL6 was downregulated in the kidneys of SHR. Either Ang II or LPS suppressed BCL6 expression in HK-2 cells. BCL6 overexpression in HK-2 cells attenuated Ang II-induced NLRP3 upregulation, inflammation and cell injury. The inhibitory effects of BCL6 overexpression on NLRP3 expression and inflammation were also observed in LPS-treated HK-2 cells. BCL6 inhibited the NLRP3 transcription via binding to the NLRP3 promoter. BCL6 knockdown with shRNA increased NLRP3 and mature IL-1β expression levels in both PBS- or Ang II-treated HK-2 cells but had no significant effects on ASC, pro-caspase-1 and pro-IL-1β expression levels. BCL6 overexpression caused by recombinant lentivirus expressing BCL6 reduced blood pressure in SHR. BCL6 overexpression prevented the upregulation of NLRP3 and mature IL-1β expression levels in the renal cortex of SHR. The results indicate that BCL6 attenuates Ang II- or LPS-induced inflammation in HK-2 cells via negative regulation of NLRP3 transcription. BCL6 overexpression in SHR reduced blood pressure, NLRP3 expression and inflammation in the renal cortex of SHR.

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Discovery of a B-Cell Lymphoma 6 Protein–Protein Interaction Inhibitor by a Biophysics-Driven Fragment-Based Approach

Cited by 45 publications

References 47 publications

Inducible knock-out of BCL6 in lymphoma cells results in tumor stasis

Inducible knock-out of BCL6 in lymphoma cells results in tumor stasis

Development of a Novel B-Cell Lymphoma 6 (BCL6) PROTAC To Provide Insight into Small Molecule Targeting of BCL6

BCL6 attenuates renal inflammation via negative regulation of NLRP3 transcription

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