Correction to Discovery of Pyrazolo[1,5-<i>a</i>]pyrimidine B-Cell Lymphoma 6 (BCL6) Binders and Optimization to High Affinity Macrocyclic Inhibitors

McCoull, William; Abrams, Roman; Anderson, Erica; Blades, Kevin; Barton, Peter; Box, Matthew; Burgess, Jonathan S.; Byth, Kate; Cao, Qing; Chuaqui, Claudio; Carbajo, Rodrigo J.; Cheung, Tony; Code, Erin; Ferguson, Andrew D.; Fillery, Shaun; Fuller, Nathan O.; Gangl, Eric; Gao, Ning; Grist, Matthew; Hargreaves, David J.; Howard, Martin; Hu, Jun; Kemmitt, Paul D.; Nelson, Jennifer E.; O’Connell, Nichole; Prince, D. Bryan; Raubo, Piotr; Rawlins, Philip; Robb, Graeme R.; Shi, Junjie; Waring, Michael J.; Whittaker, D. M.; Wylot, Marta; Zhu, Xiahui

doi:10.1021/acs.jmedchem.7b00962

Cited by 7 publications

(16 citation statements)

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“…Inhibitors of the BCL6-corepressor protein−protein interaction binding to the BCL6 BTB domain have been described. These include high-affinity peptides, 10 macrocycles, 11 as well as small molecule inhibitors. 12−17 Molecules, which induce degradation of BCL6, have also been reported, including monovalent degraders and a PROTAC.…”

Section: ■ Introductionmentioning

confidence: 99%

Into Deep Water: Optimizing BCL6 Inhibitors by Growing into a Solvated Pocket

et al. 2021

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We describe the optimization of modestly active starting points to potent inhibitors of BCL6 by growing into a subpocket, which was occupied by a network of five stably bound water molecules. Identifying potent inhibitors required not only forming new interactions in the subpocket but also perturbing the water network in a productive, potency-increasing fashion while controlling the physicochemical properties. We achieved this goal in a sequential manner by systematically probing the pocket and the water network, ultimately achieving a 100-fold improvement of activity. The most potent compounds displaced three of the five initial water molecules and formed hydrogen bonds with the remaining two. Compound 25 showed a promising profile for a lead compound with submicromolar inhibition of BCL6 in cells and satisfactory pharmacokinetic (PK) properties. Our work highlights the importance of finding productive ways to perturb existing water networks when growing into solvent-filled protein pockets.

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Section: ■ Introductionmentioning

confidence: 99%

Into Deep Water: Optimizing BCL6 Inhibitors by Growing into a Solvated Pocket

et al. 2021

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“…For example, compounds 79‐6 and FX‐1 showed encouraging biological features, while the activity of either is limited and the rhodanine‐based scaffold restricts their further drug development 197–200 . Although the inhibitors from Takeda and Astra Zeneca exhibit promising ability to disrupt the PPIs of BCL6 and corepressors (Figure 5), there is no evidence that these compounds can indeed prevent the formation of BCL6‐mediated repression complexes or reactivate the BCL6 target genes 201–203 . To overcome these insufficiencies and explore novel BCL6 inhibitors with potent bioactivities, an initial screening of in‐house libraries containing the diaminopyrimidine scaffold and other skeletons was implemented by our laboratory in consideration of the fact that the majority of known BCL6 inhibitors possess the homologous diaminopyrimidine scaffold 204 .…”

Section: Drug Discovery Strategies Targeting the Key Proteins Involve...mentioning

confidence: 99%

“…[197][198][199][200] Although the inhibitors from Takeda and Astra Zeneca exhibit promising ability to disrupt the PPIs of BCL6 and corepressors (Figure 5), there is no evidence that these compounds can indeed prevent the formation of BCL6-mediated repression complexes or reactivate the BCL6 target genes. [201][202][203] To overcome these insufficiencies and explore novel BCL6 inhibitors with potent bioactivities, an initial screening of in-house libraries containing the diaminopyrimidine scaffold and other skeletons was implemented by our laboratory in consideration of the fact that the majority of known BCL6 inhibitors possess the homologous diaminopyrimidine scaffold. 204 A compound with a diaminopyrimidine scaffold was identified as the hit that blocked the interaction between BCL6 BTB and the corepressor SMRT in a micromolar range.…”

Section: Targeting Ppismentioning

confidence: 99%

Targeting key proteins involved in transcriptional regulation for cancer therapy: Current strategies and future prospective

Pei

Guo

Peng

et al. 2022

Medicinal Research Reviews

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The key proteins involved in transcriptional regulation play convergent roles in cellular homeostasis, and their dysfunction mediates aberrant gene expressions that underline the hallmarks of tumorigenesis. As tumor progression is dependent on such abnormal regulation of transcription, it is important to discover novel chemical entities as antitumor drugs that target key tumor‐associated proteins involved in transcriptional regulation. Despite most key proteins (especially transcription factors) involved in transcriptional regulation are historically recognized as undruggable targets, multiple targeting approaches at diverse levels of transcriptional regulation, such as epigenetic intervention, inhibition of DNA‐binding of transcriptional factors, and inhibition of the protein–protein interactions (PPIs), have been established in preclinically or clinically studies. In addition, several new approaches have recently been described, such as targeting proteasomal degradation and eliciting synthetic lethality. This review will emphasize on accentuating these developing therapeutic approaches and provide a thorough conspectus of the drug development to target key proteins involved in transcriptional regulation and their impact on future oncotherapy.

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“…Herein, we analyze the recent publications about new molecules and their respective roles in vitro and in vivo applications, allowing us to identify the principal structure motifs for future novel uses. This section delves into the principal and recent advances of pyrazolo[1,5- a ]pyrimidines as an antitumor scaffold in bioactive compounds, mainly by inhibiting the reproduction of cancer cells [ 8 , 57 , 89 , 90 , 91 , 92 ] or enzymes directly related to abnormal cell reproduction [ 82 , 93 , 94 , 95 ].…”

Section: Antitumor Activitymentioning

confidence: 99%

“…McCoull and co-workers [ 89 ] built up a novel procedure for macrocyclic motifs development bearing a PP core by obtaining a series of BCL6 binders from both fragment and virtual screening. Henceforth, dislodging crystallographic water, framing new ligand protein connections, and performing a macrocyclization are actions performed to support the bioactive adaptation of the ligands.…”

Section: Antitumor Activitymentioning

confidence: 99%

Functional Pyrazolo[1,5-a]pyrimidines: Current Approaches in Synthetic Transformations and Uses As an Antitumor Scaffold

2021

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Pyrazolo[1,5-a]pyrimidine (PP) derivatives are an enormous family of N-heterocyclic compounds that possess a high impact in medicinal chemistry and have attracted a great deal of attention in material science recently due to their significant photophysical properties. Consequently, various researchers have developed different synthesis pathways for the preparation and post-functionalization of this functional scaffold. These transformations improve the structural diversity and allow a synergic effect between new synthetic routes and the possible applications of these compounds. This contribution focuses on an overview of the current advances (2015–2021) in the synthesis and functionalization of diverse pyrazolo[1,5-a]pyrimidines. Moreover, the discussion highlights their anticancer potential and enzymatic inhibitory activity, which hopefully could lead to new rational and efficient designs of drugs bearing the pyrazolo[1,5-a]pyrimidine core.

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Correction to Discovery of Pyrazolo[1,5-a]pyrimidine B-Cell Lymphoma 6 (BCL6) Binders and Optimization to High Affinity Macrocyclic Inhibitors

Cited by 7 publications

References 0 publications

Into Deep Water: Optimizing BCL6 Inhibitors by Growing into a Solvated Pocket

Into Deep Water: Optimizing BCL6 Inhibitors by Growing into a Solvated Pocket

Targeting key proteins involved in transcriptional regulation for cancer therapy: Current strategies and future prospective

Functional Pyrazolo[1,5-a]pyrimidines: Current Approaches in Synthetic Transformations and Uses As an Antitumor Scaffold

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