I04-Macromolecular Crystallography
|
Luca
Carlino
,
Peter C.
Astles
,
Bryony
Ackroyd
,
Afshan
Ahmed
,
Christina
Chan
,
Gavin W.
Collie
,
Ian L.
Dale
,
Daniel H.
O’donovan
,
Caroline
Fawcett
,
Paolo
Di Fruscia
,
Andrea
Gohlke
,
Xiaoxiao
Guo
,
Jessie
Hao-Ru Hsu
,
Bethany
Kaplan
,
Alexander G.
Milbradt
,
Sarah
Northall
,
Dušan
Petrović
,
Emma L.
Rivers
,
Elizabeth
Underwood
,
Alice
Webb
Abstract: Dysregulation of histone methyl transferase nuclear receptor-binding SET domain 2 (NSD2) has been implicated in several hematological and solid malignancies. NSD2 is a large multidomain protein that carries histone writing and histone reading functions. To date, identifying inhibitors of the enzymatic activity of NSD2 has proven challenging in terms of potency and SET domain selectivity. Inhibition of the NSD2-PWWP1 domain using small molecules has been considered as an alternative approach to reduce NSD2-unregulated activity. In this article, we present novel computational chemistry approaches, encompassing free energy perturbation coupled to machine learning (FEP/ML) models as well as virtual screening (VS) activities, to identify high-affinity NSD2 PWWP1 binders. Through these activities, we have identified the most potent NSD2-PWWP1 binder reported so far in the literature: compound 34 (pIC50 = 8.2). The compounds identified herein represent useful tools for studying the role of PWWP1 domains for inhibition of human NSD2.
|
May 2024
|
|
I04-Macromolecular Crystallography
|
James S.
Scott
,
Darren
Stead
,
Bernard
Barlaam
,
Jason
Breed
,
Rodrigo J.
Carbajo
,
Elisabetta
Chiarparin
,
Natalie
Cureton
,
Paul R. J.
Davey
,
David I.
Fisher
,
Eric T.
Gangl
,
Tyler
Grebe
,
Ryan D.
Greenwood
,
Sudhir
Hande
,
Holia
Hatoum-Mokdad
,
Samantha J.
Hughes
,
Thomas A.
Hunt
,
Tony
Johnson
,
Stefan L.
Kavanagh
,
Teresa C. M.
Klinowska
,
Carrie J. B.
Larner
,
Mandy
Lawson
,
Andrew S.
Lister
,
David
Longmire
,
Stacey
Marden
,
Thomas M.
Mcguire
,
Caroline
Mcmillan
,
Lindsay
Mcmurray
,
Christopher J.
Morrow
,
J. Willem M.
Nissink
,
Thomas A.
Moss
,
Daniel H.
O’donovan
,
Radoslaw
Polanski
,
Stephen
Stokes
,
Kumar
Thakur
,
Dawn
Trueman
,
Caroline
Truman
,
Michael J.
Tucker
,
Haixia
Wang
,
Nicky
Whalley
,
Dedong
Wu
,
Ye
Wu
,
Bin
Yang
,
Wenzhan
Yang
Diamond Proposal Number(s):
[20015]
Abstract: Herein, we report the optimization of a meta-substituted series of selective estrogen receptor degrader (SERD) antagonists for the treatment of ER+ breast cancer. Structure-based design together with the use of modeling and NMR to favor the bioactive conformation led to a highly potent series of basic SERDs with promising physicochemical properties. Issues with hERG activity resulted in a strategy of zwitterion formation and ultimately in the identification of 38. This compound was shown to be a highly potent SERD capable of effectively degrading ERα in both MCF-7 and CAMA-1 cell lines. The low lipophilicity and zwitterionic nature led to a SERD with a clean secondary pharmacology profile and no hERG activity. Favorable physicochemical properties resulted in good oral bioavailability in preclinical species and potent in vivo activity in a mouse xenograft model.
|
Feb 2023
|
|
I03-Macromolecular Crystallography
I04-Macromolecular Crystallography
|
Sharan K.
Bagal
,
Clare
Gregson
,
Daniel H.
O’ Donovan
,
Kurt G.
Pike
,
Andrew
Bloecher
,
Peter
Barton
,
Alexandra
Borodovsky
,
Erin
Code
,
Shaun M.
Fillery
,
Jessie Hao-Ru
Hsu
,
Sameer P.
Kawatkar
,
Chengzhi
Li
,
David
Longmire
,
Youfeng
Nai
,
Samuel C.
Nash
,
Andrew
Pike
,
James
Robinson
,
Jon A.
Read
,
Phillip B.
Rawlins
,
Minhui
Shen
,
Jia
Tang
,
Peng
Wang
,
Haley
Woods
,
Beth
Williamson
Diamond Proposal Number(s):
[20015]
Abstract: Aberrant activity of the histone methyltransferase polycomb repressive complex 2 (PRC2) has been linked to several cancers, with small-molecule inhibitors of the catalytic subunit of the PRC2 enhancer of zeste homologue 2 (EZH2) being recently approved for the treatment of epithelioid sarcoma (ES) and follicular lymphoma (FL). Compounds binding to the EED subunit of PRC2 have recently emerged as allosteric inhibitors of PRC2 methyltransferase activity. In contrast to orthosteric inhibitors that target EZH2, small molecules that bind to EED retain their efficacy in EZH2 inhibitor-resistant cell lines. In this paper we disclose the discovery of potent and orally bioavailable EED ligands with good solubilities. The solubility of the EED ligands was optimized through a variety of design tactics, with the resulting compounds exhibiting in vivo efficacy in EZH2-driven tumors.
|
Nov 2021
|
|
I04-1-Macromolecular Crystallography (fixed wavelength)
|
Daniel H.
O' Donovan
,
Clare
Gregson
,
Martin J.
Packer
,
Ryan
Greenwood
,
Kurt G.
Pike
,
Sameer
Kawatkar
,
Andrew
Bloecher
,
James
Robinson
,
Jon
Read
,
Erin
Code
,
Jessie Hao-Ru
Hsu
,
Minhui
Shen
,
Haley
Woods
,
Peter
Barton
,
Shaun
Fillery
,
Beth
Williamson
,
Philip B.
Rawlins
,
Sharan K.
Bagal
Abstract: Free Energy Perturbation (FEP) calculations can provide high-confidence predictions of the interaction strength between a ligand and its protein target. We sought to explore a series of triazolopyrimidines which bind to the EED subunit of the PRC2 complex as potential anticancer therapeutics, using FEP calculations to inform compound design. Combining FEP predictions with a late-stage functionalisation (LSF) inspired synthetic approach allowed us to rapidly evaluate structural modifications in a previously unexplored region of the EED binding site. This approach generated a series of novel triazolopyrimidine EED ligands with improved physicochemical properties and which inhibit PRC2 methyltransferase activity in a cancer-relevant G401 cell line.
|
May 2021
|
|
I03-Macromolecular Crystallography
|
James S.
Scott
,
Thomas A.
Moss
,
Amber
Balazs
,
Bernard
Barlaam
,
Jason
Breed
,
Rodrigo J.
Carbajo
,
Elisabetta
Chiarparin
,
Paul R. J.
Davey
,
Oona
Delpuech
,
Stephen
Fawell
,
David I.
Fisher
,
Sladjana
Gagrica
,
Eric T.
Gangl
,
Tyler
Grebe
,
Ryan D.
Greenwood
,
Sudhir
Hande
,
Holia
Hatoum-Mokdad
,
Kara
Herlihy
,
Samantha
Hughes
,
Thomas A.
Hunt
,
Hoan
Huynh
,
Sophie L. M.
Janbon
,
Tony
Johnson
,
Stefan
Kavanagh
,
Teresa
Klinowska
,
Mandy
Lawson
,
Andrew S.
Lister
,
Stacey
Marden
,
Dermot F.
Mcginnity
,
Christopher J.
Morrow
,
J. Willem M.
Nissink
,
Daniel H.
O’donovan
,
Bo
Peng
,
Radoslaw
Polanski
,
Darren S.
Stead
,
Stephen
Stokes
,
Kumar
Thakur
,
Scott R.
Throner
,
Michael J.
Tucker
,
Jeffrey
Varnes
,
Haixia
Wang
,
David M.
Wilson
,
Dedong
Wu
,
Ye
Wu
,
Bin
Yang
,
Wenzhan
Yang
Abstract: Herein we report the optimization of a series of tricyclic indazoles as selective estrogen receptor degraders (SERD) and antagonists for the treatment of ER+ breast cancer. Structure based design together with systematic investigation of each region of the molecular architecture led to the identification of N-[1-(3-fluoropropyl)azetidin-3-yl]-6-[(6S,8R)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-3H-pyrazolo[4,3-f]isoquinolin-6-yl]pyridin-3-amine (28). This compound was demonstrated to be a highly potent SERD that showed a pharmacological profile comparable to fulvestrant in its ability to degrade ERα in both MCF-7 and CAMA-1 cell lines. A stringent control of lipophilicity ensured that 28 had favorable physicochemical and preclinical pharmacokinetic properties for oral administration. This, combined with demonstration of potent in vivo activity in mouse xenograft models, resulted in progression of this compound, also known as AZD9833, into clinical trials.
|
Sep 2020
|
|
I03-Macromolecular Crystallography
I24-Microfocus Macromolecular Crystallography
|
Sarah L.
Kidd
,
Elaine
Fowler
,
Till
Reinhardt
,
Thomas
Compton
,
Natalia
Mateu
,
Hector
Newman
,
Dom
Bellini
,
Romain
Talon
,
Joseph
Mcloughlin
,
Tobias
Krojer
,
Anthony
Aimon
,
Anthony
Bradley
,
Michael
Fairhead
,
Paul
Brear
,
Laura
Diaz-Saez
,
Katherine
Mcauley
,
Hannah F.
Sore
,
Andrew
Madin
,
Daniel H.
O'Donovan
,
Kilian
Huber
,
Marko
Hyvonen
,
Frank
Von Delft
,
Christopher G.
Dowson
,
David R.
Spring
Diamond Proposal Number(s):
[18145, 15649, 14303, 14493]
Open Access
Abstract: Organic synthesis underpins the evolution of weak fragment hits into potent lead compounds. Deficiencies within current screening collections often result in the requirement of significant synthetic investment to enable multidirectional fragment growth, limiting the efficiency of the hit evolution process. Diversity-oriented synthesis (DOS)-derived fragment libraries are constructed in an efficient and modular fashion and thus are well-suited to address this challenge. To demonstrate the effective nature of such libraries within fragment-based drug discovery, we herein describe the screening of a 40-member DOS library against three functionally distinct biological targets using X-Ray crystallography. Firstly, we demonstrate the importance for diversity in aiding hit identification with four fragment binders resulting from these efforts. Moreover, we also exemplify the ability to readily access a library of analogues from cheap commercially available materials, which ultimately enabled the exploration of a minimum of four synthetic vectors from each molecule. In total, 10–14 analogues of each hit were rapidly accessed in three to six synthetic steps. Thus, we showcase how DOS-derived fragment libraries enable efficient hit derivatisation and can be utilised to remove the synthetic limitations encountered in early stage fragment-based drug discovery.
|
May 2020
|
|
I04-1-Macromolecular Crystallography (fixed wavelength)
|
Jon A.
Read
,
Jonathan
Tart
,
Philip B.
Rawlins
,
Clare
Gregson
,
Karen
Jones
,
Ning
Gao
,
Xiahui
Zhu
,
Ron
Tomlinson
,
Erin
Code
,
Tony
Cheung
,
Huawei
Chen
,
Sameer P.
Kawatkar
,
Andy
Bloecher
,
Sharan
Bagal
,
Daniel H.
O’donovan
,
James
Robinson
Abstract: Enhancer of zeste homologue 2 (EZH2), the catalytic subunit of polycomb repressive complex 2 (PRC2), regulates chromatin state and gene expression by methylating histone H3 lysine 27. EZH2 is overexpressed or mutated in various hematological malignancies and solid cancers. Our previous efforts to identify inhibitors of PRC2 methyltransferase activity by high-throughput screening (HTS) resulted in large numbers of false positives and thus a significant hit deconvolution challenge. More recently, others have reported compounds that bind to another PRC2 core subunit, EED, and allosterically inhibit EZH2 activity. This mechanism is particularly appealing as it appears to retain potency in cell lines that have acquired resistance to orthosteric EZH2 inhibition. By designing a fluorescence polarization probe based on the reported EED binding compounds, we were able to quickly and cleanly re-triage our previously challenging HTS hit list and identify novel allosteric PRC2 inhibitors.
|
Sep 2019
|
|
I04-Macromolecular Crystallography
|
Diamond Proposal Number(s):
[18548]
Open Access
Abstract: The discovery of new Protein–Protein Interaction (PPI) modulators is currently limited by the difficulties associated with the design and synthesis of selective small molecule inhibitors. Peptides are a potential solution for disrupting PPIs; however, they typically suffer from poor stability in vivo and limited tissue penetration hampering their wide spread use as new chemical biology tools and potential therapeutics. In this work, a combination of CuAAC chemistry, molecular modelling, X-ray crystallography, and biological validation allowed us to develop highly functionalised peptide PPI inhibitors of the protein CK2. The lead peptide, CAM7117, prevents the formation of the holoenzyme assembly in vitro, slows down proliferation, induces apoptosis in cancer cells and is stable in human serum. CAM7117 could aid the development of novel CK2 inhibitors acting at the interface and help to fully understand the intracellular pathways involving CK2. Importantly, the approach adopted herein could be applied to many PPI targets and has the potential to ease the study of PPIs by efficiently providing access to functionalised peptides.
|
Apr 2019
|
|