I04-Macromolecular Crystallography
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Jason D.
Shields
,
David
Baker
,
Amber Y. S.
Balazs
,
Gayathri
Bommakanti
,
Robert
Casella
,
Shenggen
Cao
,
Steve
Cook
,
Randolph A.
Escobar
,
Stephen
Fawell
,
Francis D.
Gibbons
,
Kathryn A.
Giblin
,
Frederick W.
Goldberg
,
Eric
Gosselin
,
Tyler
Grebe
,
Niresh
Hariparsad
,
Holia
Hatoum-Mokdad
,
Rachel
Howells
,
Samantha J.
Hughes
,
Anne
Jackson
,
Iswarya
Karapa Reddy
,
Jason G.
Kettle
,
Gillian M.
Lamont
,
Scott
Lamont
,
Min
Li
,
Sten O. Nilsson
Lill
,
Deanna A.
Mele
,
Anthony J.
Metrano
,
Adelphe M.
Mfuh
,
Lucas A.
Morrill
,
Bo
Peng
,
Alexander
Pflug
,
Theresa A.
Proia
,
Hadi
Rezaei
,
Ryan
Richards
,
Magdalena
Richter
,
Kevin J.
Robbins
,
Maryann
San Martin
,
Marianne
Schimpl
,
Alwin G.
Schuller
,
Li
Sha
,
Minhui
Shen
,
James E.
Sheppeck
,
Meha
Singh
,
Stephen
Stokes
,
Kun
Song
,
Yuanyuan
Sun
,
Haoran
Tang
,
David J.
Wagner
,
Jianyan
Wang
,
Yanjun
Wang
,
David M.
Wilson
,
Allan
Wu
,
Chengyan
Wu
,
Dedong
Wu
,
Ye
Wu
,
Kevin
Xu
,
Yue
Yang
,
Tieguang
Yao
,
Minwei
Ye
,
Andrew X.
Zhang
,
Hui
Zhang
,
Xiang
Zhai
,
Yanxiao
Zhou
,
Robert E.
Ziegler
,
Neil P.
Grimster
Diamond Proposal Number(s):
[20015]
Abstract: Hematopoietic progenitor kinase 1 (HPK1) is a negative regulator of the T cell receptor signaling pathway and is therefore a target of interest for immunooncology. Nonselective HPK1 inhibitors may affect other kinase components of T cell activation, blunting the beneficial impact of enhanced T cell activity that results from HPK1 inhibition itself. Here, we report the discovery of pyrazine carboxamide HPK1 inhibitors and their optimization through structure-based drug design to afford a highly selective HPK1 inhibitor, compound 24 (AZ3246). This compound induces IL-2 secretion in T cells with an EC50 of 90 nM without inhibiting antagonistic kinases, exhibits pharmacokinetic properties consistent with oral dosing, and demonstrates antitumor activity in the EMT6 syngeneic mouse model.
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Feb 2025
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I04-Macromolecular Crystallography
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Rohan
Eapen
,
Cynthia
Okoye
,
Christopher
Stubbs
,
Marianne
Schimpl
,
Thomas
Tischer
,
Eileen
Mccall
,
Maria
Zacharopoulou
,
Fernando
Ferrer
,
David
Barford
,
David
Spring
,
Cath
Lindon
,
Christopher
Phillips
,
Laura S.
Itzhaki
Diamond Proposal Number(s):
[20015]
Open Access
Abstract: E3 ubiquitin ligases engage their substrates via ‘degrons’ - short linear motifs typically located within intrinsically disordered regions of substrates. As these enzymes are large, multi-subunit complexes that generally lack natural small-molecule ligands and are hard to drug via conventional means, alternative strategies are needed to target them in diseases, and peptide-based inhibitors derived from degrons represent a promising approach. Here we explore peptide inhibitors of Cdc20, a substrate-recognition subunit and activator of the E3 ubiquitin ligase the anaphase promoting complex/cyclosome (APC/C) that is essential in mitosis and consequently of interest as an anti-cancer target. APC/C engages substrates via degrons that include the ‘Destruction box’ (D-box) motif. We used a rational design approach to construct binders containing unnatural amino acids aimed at better filling a hydrophobic pocket on the surface of Cdc20. We confirmed binding by thermal-shift assays and surface plasmon resonance and determined the structures of a number of the Cdc20-peptide complexes. Using a cellular thermal shift assay we confirmed that the D-box peptides also bind to and stabilise Cdc20 in the cell. We found that the D-box peptides inhibit ubiquitination activity of APC/CCdc20 and are more potent than the small molecule inhibitor Apcin. Lastly, these peptides function as portable degrons capable of driving the degradation of a fused fluorescent protein. Interestingly, we find that although inhibitory activity of the peptides correlates with Cdc20-binding affinity, degradation efficacy does not, which may be due to the complex nature of APC/C regulation and effects of degron binding of subunit recruitment and conformational changes. Our study lays the groundwork for the further development of these peptides as molecular therapeutics for blocking APC/C as well as potentially also for harnessing APC/C for targeted protein degradation.
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Jan 2025
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I03-Macromolecular Crystallography
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Jeffrey W.
Johannes
,
Amber Y. S.
Balazs
,
Derek
Barratt
,
Michal
Bista
,
Matthew D.
Chuba
,
Sabina
Cosulich
,
Susan E.
Critchlow
,
Sébastien L.
Degorce
,
Paolo
Di Fruscia
,
Scott D.
Edmondson
,
Kevin J.
Embrey
,
Stephen
Fawell
,
Avipsa
Ghosh
,
Sonja J.
Gill
,
Anders
Gunnarsson
,
Sudhir M.
Hande
,
Tom D.
Heightman
,
Paul
Hemsley
,
Giuditta
Illuzzi
,
Jordan
Lane
,
Carrie J. B.
Larner
,
Elisabetta
Leo
,
Lina
Liu
,
Andrew
Madin
,
Lisa
Mcwilliams
,
Mark J.
O’connor
,
Jonathan P.
Orme
,
Fiona
Pachl
,
Martin J.
Packer
,
Xiaohui
Pei
,
Andy
Pike
,
Marianne
Schimpl
,
Hongyao
She
,
Anna D.
Staniszewska
,
Verity
Talbot
,
Elizabeth
Underwood
,
Jeffrey G.
Varnes
,
Lin
Xue
,
Tieguang
Yao
,
Ke
Zhang
,
Andrew X.
Zhang
,
Xiaolan
Zheng
Diamond Proposal Number(s):
[20015]
Abstract: PARP inhibitors have attracted considerable interest in drug discovery due to the clinical success of first-generation agents such as olaparib, niraparib, rucaparib, and talazoparib. Their success lies in their ability to trap PARP to DNA; however, first-generation PARP inhibitors were not strictly optimized for trapping nor for selectivity among the PARP enzyme family. Previously we described the discovery of the second-generation PARP inhibitor AZD5305, a selective PARP1-DNA trapper. AZD5305 maintained the antitumor efficacy of first-generation PARP inhibitors while exhibiting lower hematological toxicity. Recently, there has been interest in central nervous system (CNS)-penetrant PARP inhibitors for CNS malignancies and other neurological conditions; however, AZD5305 is not CNS penetrant. Herein we describe the discovery and optimization of a series of CNS-penetrant, PARP1-selective inhibitors and PARP1-DNA trappers, culminating in the discovery of AZD9574, a compound that maintains the PARP1 selectivity of AZD5305 with improved permeability, reduced efflux, and increased CNS penetration.
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Dec 2024
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I04-Macromolecular Crystallography
I24-Microfocus Macromolecular Crystallography
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Taylor R.
Quinn
,
Kathryn A.
Giblin
,
Clare
Thomson
,
Jeffrey A.
Boerth
,
Gayathri
Bommakanti
,
Erin
Braybrooke
,
Christina
Chan
,
Alex J.
Chinn
,
Erin
Code
,
Caifeng
Cui
,
Yukai
Fan
,
Neil P.
Grimster
,
Keishi
Kohara
,
Michelle L.
Lamb
,
Lina
Ma
,
Adelphe M.
Mfuh
,
Graeme R.
Robb
,
Kevin J.
Robbins
,
Marianne
Schimpl
,
Haoran
Tang
,
Jamie
Ware
,
Gail L.
Wrigley
,
Lin
Xue
,
Yun
Zhang
,
Huimin
Zhu
,
Samantha J.
Hughes
Diamond Proposal Number(s):
[20015]
Abstract: Casitas B-lymphoma proto-oncogene-b (Cbl-b) is a RING finger E3 ligase that has an important role in effector T cell function, acting as a negative regulator of T cell, natural killer (NK) cell, and B cell activation. A discovery effort toward Cbl-b inhibitors was pursued in which a generative AI design engine, REINVENT, was combined with a medicinal chemistry structure-based design to discover novel inhibitors of Cbl-b. Key to the success of this effort was the evolution of the “Design” phase of the Design-Make-Test-Analyze cycle to involve iterative rounds of an in silico structure-based drug design, strongly guided by physics-based affinity prediction and machine learning DMPK predictive models, prior to selection for synthesis. This led to the accelerated discovery of a potent series of carbamate Cbl-b inhibitors.
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Aug 2024
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I03-Macromolecular Crystallography
I04-Macromolecular Crystallography
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Stephen J.
Atkinson
,
Sharan K.
Bagal
,
Argyrides
Argyrou
,
Sean
Askin
,
Tony
Cheung
,
Elisabetta
Chiarparin
,
Muireann
Coen
,
Iain T.
Collie
,
Ian L.
Dale
,
Claudia
De Fusco
,
Keith
Dillman
,
Laura
Evans
,
Lyman J.
Feron
,
Alison J.
Foster
,
Michael
Grondine
,
Vasudev
Kantae
,
Gillian M.
Lamont
,
Scott
Lamont
,
James T.
Lynch
,
Sten
Nilsson Lill
,
Graeme R.
Robb
,
Jamal
Saeh
,
Marianne
Schimpl
,
James S.
Scott
,
James
Smith
,
Bharath
Srinivasan
,
Sharon
Tentarelli
,
Mercedes
Vazquez-Chantada
,
David
Wagner
,
Jarrod J.
Walsh
,
David
Watson
,
Beth
Williamson
Diamond Proposal Number(s):
[20015]
Abstract: The optimization of an allosteric fragment, discovered by differential scanning fluorimetry, to an in vivo MAT2a tool inhibitor is discussed. The structure-based drug discovery approach, aided by relative binding free energy calculations, resulted in AZ’9567 (21), a potent inhibitor in vitro with excellent preclinical pharmacokinetic properties. This tool showed a selective antiproliferative effect on methylthioadenosine phosphorylase (MTAP) KO cells, both in vitro and in vivo, providing further evidence to support the utility of MAT2a inhibitors as potential anticancer therapies for MTAP-deficient tumors.
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Mar 2024
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I04-Macromolecular Crystallography
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Adelphe M.
Mfuh
,
Jeffrey A.
Boerth
,
Gayathri
Bommakanti
,
Christina
Chan
,
Alex J.
Chinn
,
Erin
Code
,
Patrick J.
Fricke
,
Kathryn A.
Giblin
,
Andrea
Gohlke
,
Catherine
Hansel
,
Niresh
Hariparsad
,
Samantha J.
Hughes
,
Meizhong
Jin
,
Vasudev
Kantae
,
Stefan L.
Kavanagh
,
Michelle L.
Lamb
,
Jordan
Lane
,
Rachel
Moore
,
Taranee
Puri
,
Taylor R.
Quinn
,
Iswarya
Reddy
,
Graeme R.
Robb
,
Kevin J.
Robbins
,
Miguel
Gancedo Rodrigo
,
Marianne
Schimpl
,
Baljinder
Singh
,
Meha
Singh
,
Haoran
Tang
,
Clare
Thomson
,
Jarrod J.
Walsh
,
Jamie
Ware
,
Iain D. G.
Watson
,
Min-Wei
Ye
,
Gail L.
Wrigley
,
Andrew X.
Zhang
,
Yun
Zhang
,
Neil P.
Grimster
Diamond Proposal Number(s):
[20015]
Abstract: Casitas B-lymphoma proto-oncogene-b (Cbl-b), a member of the Cbl family of RING finger E3 ubiquitin ligases, has been demonstrated to play a central role in regulating effector T-cell function. Multiple studies using gene-targeting approaches have provided direct evidence that Cbl-b negatively regulates T, B, and NK cell activation via a ubiquitin-mediated protein modulation. Thus, inhibition of Cbl-b ligase activity can lead to immune activation and has therapeutic potential in immuno-oncology. Herein, we describe the discovery and optimization of an arylpyridone series as Cbl-b inhibitors by structure-based drug discovery to afford compound 31. This compound binds to Cbl-b with an IC50 value of 30 nM and induces IL-2 production in T-cells with an EC50 value of 230 nM. Compound 31 also shows robust intracellular target engagement demonstrated through inhibition of Cbl-b autoubiquitination, inhibition of ubiquitin transfer to ZAP70, and the cellular modulation of phosphorylation of a downstream signal within the TCR axis.
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Jan 2024
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I04-Macromolecular Crystallography
I24-Microfocus Macromolecular Crystallography
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Jeffrey A.
Boerth
,
Alex J.
Chinn
,
Marianne
Schimpl
,
Gayathri
Bommakanti
,
Christina
Chan
,
Erin L.
Code
,
Kathryn A.
Giblin
,
Andrea
Gohlke
,
Catherine S.
Hansel
,
Meizhong
Jin
,
Stefan L.
Kavanagh
,
Michelle L.
Lamb
,
Jordan S.
Lane
,
Carrie J. B.
Larner
,
Adelphe M.
Mfuh
,
Rachel K.
Moore
,
Taranee
Puri
,
Taylor R.
Quinn
,
Minwei
Ye
,
Kevin J.
Robbins
,
Miguel
Gancedo-Rodrigo
,
Haoran
Tang
,
Jarrod
Walsh
,
Jamie
Ware
,
Gail L.
Wrigley
,
Iswarya Karapa
Reddy
,
Yun
Zhang
,
Neil P.
Grimster
Diamond Proposal Number(s):
[20015]
Abstract: Casitas B-lineage lymphoma proto-oncogene-b (Cbl-b) is a RING finger E3 ligase that is responsible for repressing T-cell, natural killer (NK) cell, and B-cell activation. The robust antitumor activity observed in Cbl-b deficient mice arising from elevated T-cell and NK-cell activity justified our discovery effort toward Cbl-b inhibitors that might show therapeutic promise in immuno-oncology, where activation of the immune system can drive the recognition and killing of cancer cells. We undertook a high-throughput screening campaign followed by structure-enabled optimization to develop a novel benzodiazepine series of potent Cbl-b inhibitors. This series displayed nanomolar levels of biochemical potency, as well as potent T-cell activation. The functional activity of this class of Cbl-b inhibitors was further corroborated with ubiquitin-based cellular assays.
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Nov 2023
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I03-Macromolecular Crystallography
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Frederick W.
Goldberg
,
Attilla K. T.
Ting
,
David
Beattie
,
Gillian M.
Lamont
,
Charlene
Fallan
,
M. Raymond V.
Finlay
,
Beth
Williamson
,
Marianne
Schimpl
,
Alexander R.
Harmer
,
Oladipupo B.
Adeyemi
,
Pär
Nordell
,
Anna S.
Cronin
,
Mercedes
Vazquez-Chantada
,
Derek
Barratt
,
Antonio
Ramos-Montoya
,
Elaine B.
Cadogan
,
Barry R.
Davies
Diamond Proposal Number(s):
[20015]
Abstract: The DNA-PK complex is activated by double-strand DNA breaks and regulates the non-homologous end-joining repair pathway; thus, targeting DNA-PK by inhibiting the DNA-PK catalytic subunit (DNA-PKcs) is potentially a useful therapeutic approach for oncology. A previously reported series of neutral DNA-PKcs inhibitors were modified to incorporate a basic group, with the rationale that increasing the volume of distribution while maintaining good metabolic stability should increase the half-life. However, adding a basic group introduced hERG activity, and basic compounds with modest hERG activity (IC50 = 10–15 μM) prolonged QTc (time from the start of the Q wave to the end of the T wave, corrected by heart rate) in an anaesthetized guinea pig cardiovascular model. Further optimization was necessary, including modulation of pKa, to identify compound 18, which combines low hERG activity (IC50 = 75 μM) with excellent kinome selectivity and favorable pharmacokinetic properties.
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Jul 2022
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I03-Macromolecular Crystallography
|
William
Mccoull
,
Scott
Boyd
,
Martin R.
Brown
,
Muireann
Coen
,
Olga
Collingwood
,
Nichola L.
Davies
,
Ann
Doherty
,
Gary
Fairley
,
Kristin
Goldberg
,
Elizabeth
Hardaker
,
Guang
He
,
Edward J.
Hennessy
,
Philip
Hopcroft
,
George
Hodgson
,
Anne
Jackson
,
Xiefeng
Jiang
,
Ankur
Karmokar
,
Anne-Laure
Lainé
,
Nicola
Lindsay
,
Yumeng
Mao
,
Roshini
Markandu
,
Lindsay
Mcmurray
,
Neville
Mclean
,
Lorraine
Mooney
,
Helen
Musgrove
,
J. Willem M.
Nissink
,
Alexander
Pflug
,
Venkatesh Pilla
Reddy
,
Philip B.
Rawlins
,
Emma
Rivers
,
Marianne
Schimpl
,
Graham F.
Smith
,
Sharon
Tentarelli
,
Jon
Travers
,
Robert I.
Troup
,
Josephine
Walton
,
Cheng
Wang
,
Stephen
Wilkinson
,
Beth
Williamson
,
Jon
Winter-Holt
,
Dejian
Yang
,
Yuting
Zheng
,
Qianxiu
Zhu
,
Paul D.
Smith
Diamond Proposal Number(s):
[17180]
Abstract: Inhibition of Mer and Axl kinases has been implicated as a potential way to improve the efficacy of current immuno-oncology therapeutics by restoring the innate immune response in the tumor microenvironment. Highly selective dual Mer/Axl kinase inhibitors are required to validate this hypothesis. Starting from hits from a DNA-encoded library screen, we optimized an imidazo[1,2-a]pyridine series using structure-based compound design to improve potency and reduce lipophilicity, resulting in a highly selective in vivo probe compound 32. We demonstrated dose-dependent in vivo efficacy and target engagement in Mer- and Axl-dependent efficacy models using two structurally differentiated and selective dual Mer/Axl inhibitors. Additionally, in vivo efficacy was observed in a preclinical MC38 immuno-oncology model in combination with anti-PD1 antibodies and ionizing radiation.
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Sep 2021
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I03-Macromolecular Crystallography
I04-1-Macromolecular Crystallography (fixed wavelength)
|
Jeffrey W.
Johannes
,
Amber
Balazs
,
Derek
Barratt
,
Michal
Bista
,
Matthew D.
Chuba
,
Sabina
Cosulich
,
Susan E.
Critchlow
,
Sébastien L.
Degorce
,
Paolo
Di Fruscia
,
Scott D.
Edmondson
,
Kevin
Embrey
,
Stephen
Fawell
,
Avipsa
Ghosh
,
Sonja J.
Gill
,
Anders
Gunnarsson
,
Sudhir M.
Hande
,
Tom D.
Heightman
,
Paul
Hemsley
,
Giuditta
Illuzzi
,
Jordan
Lane
,
Carrie
Larner
,
Elisabetta
Leo
,
Lina
Liu
,
Andrew
Madin
,
Scott
Martin
,
Lisa
Mcwilliams
,
Mark J.
O'Connor
,
Jonathan P.
Orme
,
Fiona
Pachl
,
Martin J.
Packer
,
Xiaohui
Pei
,
Andrew
Pike
,
Marianne
Schimpl
,
Hongyao
She
,
Anna D.
Staniszewska
,
Verity
Talbot
,
Elizabeth
Underwood
,
Jeffrey G.
Varnes
,
Lin
Xue
,
Tieguang
Yao
,
Ke
Zhang
,
Andrew X.
Zhang
,
Xiaolan
Zheng
Diamond Proposal Number(s):
[14631, 17180, 20015]
Abstract: Poly-ADP-ribose-polymerase (PARP) inhibitors have achieved regulatory approval in oncology for homologous recombination repair deficient tumors including BRCA mutation. However, some have failed in combination with first-line chemotherapies, usually due to overlapping hematological toxicities. Currently approved PARP inhibitors lack selectivity for PARP1 over PARP2 and some other 16 PARP family members, and we hypothesized that this could contribute to toxicity. Recent literature has demonstrated that PARP1 inhibition and PARP1–DNA trapping are key for driving efficacy in a BRCA mutant background. Herein, we describe the structure- and property-based design of 25 (AZD5305), a potent and selective PARP1 inhibitor and PARP1–DNA trapper with excellent in vivo efficacy in a BRCA mutant HBCx-17 PDX model. Compound 25 is highly selective for PARP1 over other PARP family members, with good secondary pharmacology and physicochemical properties and excellent pharmacokinetics in preclinical species, with reduced effects on human bone marrow progenitor cells in vitro.
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Sep 2021
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