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Identification of a Chemical Probe for Family VIII Bromodomains through Optimization of a Fragment Hit.

ABSTRACT: The acetyl post-translational modification of chromatin at selected histone lysine residues is interpreted by an acetyl-lysine specific interaction with bromodomain reader modules. Here we report the discovery of the potent, acetyl-lysine-competitive, and cell active inhibitor PFI-3 that binds to certain family VIII bromodomains while displaying significant, broader bromodomain family selectivity. The high specificity of PFI-3 for family VIII was achieved through a novel bromodomain binding mode of a phenolic headgroup that led to the unusual displacement of water molecules that are generally retained by most other bromodomain inhibitors reported to date. The medicinal chemistry program that led to PFI-3 from an initial fragment screening hit is described in detail, and additional analogues with differing family VIII bromodomain selectivity profiles are also reported. We also describe the full pharmacological characterization of PFI-3 as a chemical probe, along with phenotypic data on adipocyte and myoblast cell differentiation assays.

SUBMITTER: Gerstenberger BS

PROVIDER: S-EPMC5034155 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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Identification of a Chemical Probe for Family VIII Bromodomains through Optimization of a Fragment Hit.

Gerstenberger Brian S BS Trzupek John D JD Tallant Cynthia C Fedorov Oleg O Filippakopoulos Panagis P Brennan Paul E PE Fedele Vita V Martin Sarah S Picaud Sarah S Rogers Catherine C Parikh Mihir M Taylor Alexandria A Samas Brian B O'Mahony Alison A Berg Ellen E Pallares Gabriel G Torrey Adam D AD Treiber Daniel K DK Samardjiev Ivan J IJ Nasipak Brian T BT Padilla-Benavides Teresita T Wu Qiong Q Imbalzano Anthony N AN Nickerson Jeffrey A JA Bunnage Mark E ME Müller Susanne S Knapp Stefan S Owen Dafydd R DR

Journal of medicinal chemistry 20160503 10

The acetyl post-translational modification of chromatin at selected histone lysine residues is interpreted by an acetyl-lysine specific interaction with bromodomain reader modules. Here we report the discovery of the potent, acetyl-lysine-competitive, and cell active inhibitor PFI-3 that binds to certain family VIII bromodomains while displaying significant, broader bromodomain family selectivity. The high specificity of PFI-3 for family VIII was achieved through a novel bromodomain binding mode ...[more]

PMID: 27115555

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Project description:In early-stage drug discovery, the hit-to-lead optimization (or "hit expansion") stage entails starting from a newly identified active compound and improving its potency or other properties. Traditionally, this process relies on synthesizing and evaluating a series of analogues to build up structure-activity relationships. Here, we describe a computational strategy focused on kinase inhibitors, intended to expedite the process of identifying analogues with improved potency. Our protocol begins from an inhibitor of the target kinase and generalizes the synthetic route used to access it. By searching for commercially available replacements for the individual building blocks used to make the parent inhibitor, we compile an enumerated library of compounds that can be accessed using the same chemical transformations; these huge libraries can exceed many millions─or billions─of compounds. Because the resulting libraries are much too large for explicit virtual screening, we instead consider alternate approaches to identify the top-scoring compounds. We find that contributions from individual substituents are well described by a pairwise additivity approximation, provided that the corresponding fragments position their shared core in precisely the same way relative to the binding site. This key insight allows us to determine which fragments are suitable for merging into single new compounds and which are not. Further, the use of pairwise approximation allows interaction energies to be assigned to each compound in the library without the need for any further structure-based modeling: interaction energies instead can be reliably estimated from the energies of the component fragments, and the reduced computational requirements allow for flexible energy minimizations that allow the kinase to respond to each substitution. We demonstrate this protocol using libraries built from six representative kinase inhibitors drawn from the literature, which target five different kinases: CDK9, CHK1, CDK2, EGFRT790M, and ACK1. In each example, the enumerated library includes additional analogues reported by the original study to have activity, and these analogues are successfully prioritized within the library. We envision that the insights from this work can facilitate the rapid assembly and screening of increasingly large libraries for focused hit-to-lead optimization. To enable adoption of these methods and to encourage further analyses, we disseminate the computational tools needed to deploy this protocol.

Dataset Information

Identification of a Chemical Probe for Family VIII Bromodomains through Optimization of a Fragment Hit.

Publications

Identification of a Chemical Probe for Family VIII Bromodomains through Optimization of a Fragment Hit.

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