Identification of a BAZ2A Bromodomain Hit Compound by Fragment Joining

Vedove, Andrea Dalle; Cazzanelli, Giulia; Corsi, Jessica; Sedykh, Maria; D’Agostino, Vito; Caflisch, Amedeo; Lolli, G.

doi:10.1021/acsbiomedchemau.1c00016

Cited by 3 publications

(3 citation statements)

References 23 publications

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“…The tail of the second UP39 molecule protrudes away from the bromodomain and is stabilized by additional interactions with a BAZ2A symmetry‐related copy. This four‐layer organization is also observed in the different CBP/BAZ2 cross‐reactive inhibitor UZH23, described in the supplementary material (Figure S4 ), and in additional BAZ2A hit compounds recently identified (Dalle Vedove et al, 2021 , 2022 ). These last advantageously exploit both self‐stacking and H‐bond to Asn1823, which could be achieved in UP39 or UZH23 derivatives.…”

Section: Resultssupporting

confidence: 63%

Reevaluation of bromodomain ligands targeting BAZ2A

Cazzanelli,

Vedove,

Parolin

et al. 2023

Protein Science

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BAZ2A promotes migration and invasion in prostate cancer. Two chemical probes, the specific BAZ2‐ICR and the BAZ2/BRD9 cross‐reactive GSK2801, interfere with the recognition of acetylated lysines in histones by the bromodomains of BAZ2A and of its BAZ2B paralog. The two chemical probes were tested in prostate cancer cell lines with opposite androgen susceptibility. BAZ2‐ICR and GSK2801 showed different cellular efficacies in accordance with their unequal selectivity profiles. Concurrent inhibition of BAZ2 and BRD9 did not reproduce the effects observed with GSK2801, indicating possible off‐targets for this chemical probe. On the other hand, the single BAZ2 inhibition by BAZ2‐ICR did not phenocopy genetic ablation, demonstrating that bromodomain interference is not sufficient to strongly affect BAZ2A functionality and suggesting a PROTAC‐based chemical ablation as an alternative optimization strategy and a possible therapeutic approach. In this context, we also present the crystallographic structures of BAZ2A in complex with the above chemical probes. Binding poses of TP‐238 and GSK4027, chemical probes for the bromodomain subfamily I, and of two ligands of the CBP/EP300 bromodomains identify additional headgroups for the development of BAZ2A ligands.This article is protected by copyright. All rights reserved.

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Section: Resultssupporting

confidence: 63%

Reevaluation of bromodomain ligands targeting BAZ2A

Cazzanelli,

Vedove,

Parolin

et al. 2023

Protein Science

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“…Finally, 104 shows good selectivity over the closely related BAZ2B bromodomain, and the highest achieved so far, with an IC 50 of 33.5 μM, as determined by AlphaScreen (Figure S6). As compared with previous screening campaigns, ,, such selectivity was obtained in the context of a reasonable LE and optimal log P , log D , and LLE.…”

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confidence: 58%

“…These last two also reproduce the four-layer sandwich observed in 104 , with the two aromatic rings squeezed between Trp1816 and Leu1826 ( Figure 5 c). 9 , 10 , 17 The decreased ligand efficiency (LE) of 104 compared to the parent compounds 25 and 47 (0.24 vs 0.31 and 0.29 kcal/mol per heavy atom, respectively) is compensated however by a more favorable lipophilic ligand efficiency (LLE, 4.0 vs 2.4 and 1.9, respectively).…”

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confidence: 99%

Identification of a BAZ2A-Bromodomain Hit Compound by Fragment Growing

Vedove

Cazzanelli

Batiste

et al. 2022

ACS Med. Chem. Lett.

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BAZ2A is an epigenetic regulator affecting transcription of ribosomal RNA. It is overexpressed in aggressive and recurrent prostate cancer, promoting cellular migration. Its bromodomain is characterized by a shallow and difficult-to-drug pocket. Here, we describe a structure-based fragment-growing campaign for the identification of ligands of the BAZ2A bromodomain. By combining docking, competition binding assays, and protein crystallography, we have extensively explored the interactions of the ligands with the rim of the binding pocket, and in particular ionic interactions with the side chain of Glu1820, which is unique to BAZ2A. We present 23 high-resolution crystal structures of the holo BAZ2A bromodomain and analyze common bromodomain/ligand motifs and favorable intraligand interactions. Binding of some of the compounds is enantiospecific, with affinity in the low micromolar range. The most potent ligand has an equilibrium dissociation constant of 7 μM and a good selectivity over the paralog BAZ2B bromodomain.

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Biochemical and cellular insights into the Baz2B protein, a non-catalytic subunit of the chromatin remodeling complex

Breindl,

Spitzer,

Gerasimaitė

et al. 2023

Nucleic Acids Research

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Baz2B is a regulatory subunit of the ATP-dependent chromatin remodeling complexes BRF1 and BRF5, which control access to DNA during DNA-templated processes. Baz2B has been implicated in several diseases and also in unhealthy ageing, however limited information is available on the domains and cellular roles of Baz2B. To gain more insight into the Baz2B function, we biochemically characterized the TAM (Tip5/ARBP/MBD) domain with the auxiliary AT-hook motifs and the bromodomain (BRD). We observed alterations in histone code recognition in bromodomains carrying cancer-associated point mutations, suggesting their potential involvement in disease. Furthermore, the depletion of Baz2B in the Hap1 cell line resulted in altered cell morphology, reduced colony formation and perturbed transcriptional profiles. Despite that, super-resolution microscopy images revealed no changes in the overall chromatin structure in the absence of Baz2B. These findings provide insights into the biological function of Baz2B.

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Identification of a BAZ2A Bromodomain Hit Compound by Fragment Joining

Cited by 3 publications

References 23 publications

Reevaluation of bromodomain ligands targeting BAZ2A

Reevaluation of bromodomain ligands targeting BAZ2A

Identification of a BAZ2A-Bromodomain Hit Compound by Fragment Growing

Biochemical and cellular insights into the Baz2B protein, a non-catalytic subunit of the chromatin remodeling complex

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