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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William
Mccoull
,
Clare
Thomson
,
Erin
Braybrooke
,
Christina
Chan
,
Nicola
Colclough
,
Miguel A.
Cortés González
,
Sabina
Cosulich
,
Nichola L.
Davies
,
Nicolas
Floc’h
,
Ryan
Greenwood
,
David
Hargreaves
,
Peng
Huang
,
Thomas A.
Hunt
,
Tony
Johnson
,
Peter
Johnström
,
Jason G.
Kettle
,
Mikhail
Kondrashov
,
Demetrios H.
Kostomiris
,
Songlei
Li
,
Andrew
Lister
,
Scott
Martin
,
Darren
Mckerrecher
,
Neville
Mclean
,
J. Willem M.
Nissink
,
Jonathan P.
Orme
,
Paige
Orwig
,
Martin J.
Packer
,
Stuart
Pearson
,
Lina
Qin
,
Catarina
Felisberto-Rodrigues
,
Adriana
Savoca
,
Magnus
Schou
,
Stephen
Stokes
,
Aisha M.
Swaih
,
Sara
Talbot
,
Michael J.
Tucker
,
Richard A.
Ward
,
Emma
Wadforth
,
Chunli
Wang
,
Joanne
Wilson
,
Yawen
Yang
Abstract: Despite recent advances in the inhibition of EGFR (epidermal growth factor receptor), there remains a clinical need for new EGFR Exon20 insertion (Ex20Ins) inhibitors that spare EGFR WT. Herein, we report the discovery and optimization of two chemical series leading to ether 23 and biaryl 36 as potent, selective, and brain-penetrant inhibitors of Ex20Ins mutants. Building on our earlier discovery of alkyne 5 which allowed access to CNS property space for an Ex20Ins inhibitor, we utilized structure-based design to move to lower lipophilicity and lower CLint compounds while maintaining a WT selectivity margin. During optimization, aldehyde oxidase (AO) metabolism was identified as a human clearance risk, and through SAR exploration, lower AO metabolism was achieved. Potency and WT margin were optimized across a range of Ex20Ins mutants including the potential acquired resistance T790M mutant and efficacy demonstrated in an LXF2478 Ex20Ins ASV model with margin to EGFR WT in vivo.
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Jan 2025
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I04-Macromolecular Crystallography
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Simon C. C.
Lucas
,
Alexander G.
Milbradt
,
J. Henry
Blackwell
,
Silvia
Bonomo
,
Andrew
Brierley
,
Doyle J.
Cassar
,
Jared
Freeman
,
Thomas E.
Hadfield
,
Lucas A.
Morrill
,
Rick
Riemens
,
Sunil
Sarda
,
Stefan
Schiesser
,
Daniel
Wiktelius
,
Samiyah
Ahmed
,
Mark J.
Bostock
,
Ulf
Börjesson
,
Claudia
De Fusco
,
Carine
Guerot
,
David
Hargreaves
,
Sarah
Hewitt
,
Michelle L.
Lamb
,
Nancy
Su
,
Ryan
Whatling
,
Matthew
Wheeler
,
Jason G.
Kettle
Abstract: Covalent hit identification is a viable approach to identify chemical starting points against difficult-to-drug targets. While most researchers screen libraries of <2k electrophilic fragments, focusing on lead-like compounds can be advantageous in terms of finding hits with improved affinity and with a better chance of identifying cryptic pockets. However, due to the increased molecular complexity, larger numbers of compounds (>10k) are desirable to ensure adequate coverage of chemical space. Herein, the approach taken to build a library of 12k covalent lead-like compounds is reported, utilizing legacy compounds, robust library chemistry, and acquisitions. The lead-like covalent library was screened against the antiapoptotic protein Bfl-1, and six promising hits that displaced the BIM peptide from the PPI interface were identified. Intriguingly, X-ray crystallography of lead-like compound 8 showed that it binds to a previously unobserved conformation of the Bfl-1 protein and is an ideal starting point for the optimization of Bfl-1 inhibitors.
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Jun 2024
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I04-Macromolecular Crystallography
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Jason G.
Kettle
,
Sharan K.
Bagal
,
Derek
Barratt
,
Michael S.
Bodnarchuk
,
Scott
Boyd
,
Erin
Braybrooke
,
Jason
Breed
,
Doyle J.
Cassar
,
Sabina
Cosulich
,
Michael
Davies
,
Nichola L.
Davies
,
Chao
Deng
,
Andrew
Eatherton
,
Laura
Evans
,
Lyman J.
Feron
,
Shaun
Fillery
,
Emma
Gleave
,
Frederick W.
Goldberg
,
Miguel A.
Cortés González
,
Carine
Guerot
,
Afreen
Haider
,
Stephanie
Harlfinger
,
Rachel
Howells
,
Anne
Jackson
,
Peter
Johnström
,
Paul D.
Kemmitt
,
Alex
Koers
,
Mikhail
Kondrashov
,
Gillian M.
Lamont
,
Scott
Lamont
,
Hilary J.
Lewis
,
Libin
Liu
,
Megan
Mylrea
,
Samuel
Nash
,
Michael J.
Niedbala
,
Alison
Peter
,
Christopher
Phillips
,
Kurt
Pike
,
Piotr
Raubo
,
Graeme R.
Robb
,
Sarah
Ross
,
Matthew G.
Sanders
,
Magnus
Schou
,
Iain
Simpson
,
Oliver
Steward
Diamond Proposal Number(s):
[20015]
Abstract: The glycine to cysteine mutation at codon 12 of Kirsten rat sarcoma (KRAS) represents an Achilles heel that has now rendered this important GTPase druggable. Herein, we report our structure-based drug design approach that led to the identification of 14, AZD4747, a clinical development candidate for the treatment of KRASG12C-positive tumors, including the treatment of central nervous system (CNS) metastases. Building on our earlier discovery of C5-tethered quinazoline AZD4625, excision of a usually critical pyrimidine ring yielded a weak but brain-penetrant start point which was optimized for potency and DMPK. Key design principles and measured parameters that give high confidence in CNS exposure are discussed. During optimization, divergence between rodent and non-rodent species was observed in CNS exposure, with primate PET studies ultimately giving high confidence in the expected translation to patients. AZD4747 is a highly potent and selective inhibitor of KRASG12C with an anticipated low clearance and high oral bioavailability profile in humans.
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Jul 2023
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I04-Macromolecular Crystallography
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Jason G.
Kettle
,
Sharan K.
Bagal
,
Sue
Bickerton
,
Michael S.
Bodnarchuk
,
Scott
Boyd
,
Jason
Breed
,
Rodrigo J.
Carbajo
,
Doyle J.
Cassar
,
Atanu
Chakraborty
,
Sabina
Cosulich
,
Iain
Cumming
,
Michael
Davies
,
Nichola L.
Davies
,
Andrew
Eatherton
,
Laura
Evans
,
Lyman
Feron
,
Shaun
Fillery
,
Emma S.
Gleave
,
Frederick W.
Goldberg
,
Lyndsey
Hanson
,
Stephanie
Harlfinger
,
Martin
Howard
,
Rachel
Howells
,
Anne
Jackson
,
Paul
Kemmitt
,
Gillian
Lamont
,
Scott
Lamont
,
Hilary J.
Lewis
,
Libin
Liu
,
Michael J.
Niedbala
,
Christopher
Phillips
,
Radek
Polanski
,
Piotr
Raubo
,
Graeme
Robb
,
David M.
Robinson
,
Sarah
Ross
,
Matthew G.
Sanders
,
Michael
Tonge
,
Rebecca
Whiteley
,
Stephen
Wilkinson
,
Junsheng
Yang
,
Wenman
Zhang
Diamond Proposal Number(s):
[20015]
Abstract: KRAS is an archetypal high-value intractable oncology drug target. The glycine to cysteine mutation at codon 12 represents an Achilles heel that has now rendered this important GTPase druggable. Herein, we report our structure-based drug design approach that led to the identification of 21, AZD4625, a clinical development candidate for the treatment of KRASG12C positive tumors. Highlights include a quinazoline tethering strategy to lock out a bio-relevant binding conformation and an optimization strategy focused on the reduction of extrahepatic clearance mechanisms seen in preclinical species. Crystallographic analysis was also key in helping to rationalize unusual structure–activity relationship in terms of ring size and enantio-preference. AZD4625 is a highly potent and selective inhibitor of KRASG12C with an anticipated low clearance and high oral bioavailability profile in humans.
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May 2022
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I03-Macromolecular Crystallography
I04-Macromolecular Crystallography
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Kirsten
Mcaulay
,
Emily A.
Hoyt
,
Morgan
Thomas
,
Marianne
Schimpl
,
Michael S.
Bodnarchuk
,
Hilary J.
Lewis
,
Derek
Barratt
,
Deepa
Bhavsar
,
David M.
Robinson
,
Michael J.
Deery
,
Derek
Ogg
,
Gonçalo J. I.
Bernardes
,
Richard A.
Ward
,
Michael J.
Waring
,
Jason G.
Kettle
Diamond Proposal Number(s):
[12419, 20015]
Abstract: With a resurgence in interest in covalent drugs, there is need to identify new moieties capable of cysteine bond formation that are differentiated from commonly employed systems such as acrylamide. Herein, we report on the discovery of new alkynyl benzoxazine and dihydroquinazoline moieties capable of covalent reaction with cysteine. Their utility as alternative electrophilic warheads for chemical biological probes and drug molecules is demonstrated through site-selective protein modification and incorporation into kinase drug scaffolds. A potent covalent inhibitor of JAK3 kinase was identified with superior selectivity across the kinome and improvements in in vitro pharmacokinetic profile relative to the related acrylamide-based inhibitor. In addition, the use of a novel heterocycle as cysteine reactive warhead is employed to target Cys788 in c-KIT where acrylamide has previously failed to form covalent interactions. These new reactive and selective heterocyclic warheads supplement the current repertoire for cysteine covalent modification whilst avoiding some of the limitations generally associated with established moieties.
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May 2020
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I03-Macromolecular Crystallography
I04-Macromolecular Crystallography
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Jason G.
Kettle
,
Sharan K.
Bagal
,
Sue
Bickerton
,
Michael S.
Bodnarchuk
,
Jason
Breed
,
Rodrigo J.
Carbajo
,
Doyle J.
Cassar
,
Atanu
Chakraborty
,
Sabina
Cosulich
,
Iain
Cumming
,
Michael
Davies
,
Andrew
Eatherton
,
Laura
Evans
,
Lyman
Feron
,
Shaun
Fillery
,
Emma
Gleave
,
Frederick W.
Goldberg
,
Stephanie
Harlfinger
,
Lyndsey
Hanson
,
Martin
Howard
,
Rachel
Howells
,
Anne
Jackson
,
Paul
Kemmitt
,
Jennifer K.
Kingston
,
Scott
Lamont
,
Hilary J.
Lewis
,
Songlei
Li
,
Libin
Liu
,
Derek
Ogg
,
Christopher
Phillips
,
Radek
Polanski
,
Graeme
Robb
,
David
Robinson
,
Sarah
Ross
,
James M.
Smith
,
Michael
Tonge
,
Rebecca
Whiteley
,
Junsheng
Yang
,
Longfei
Zhang
,
Xiliang
Zhao
Diamond Proposal Number(s):
[20015]
Abstract: Attempts to directly drug the important oncogene KRAS have met with limited success despite numerous efforts across industry and academia. The KRASG12C mutant represents an “Achilles heel” and has recently yielded to covalent targeting with small molecules that bind the mutant cysteine and create an allosteric pocket on GDP-bound RAS, locking it in an inactive state. A weak inhibitor at this site was optimized through conformational locking of a piperazine–quinazoline motif and linker modification. Subsequent introduction of a key methyl group to the piperazine resulted in enhancements in potency, permeability, clearance, and reactivity, leading to identification of a potent KRASG12C inhibitor with high selectivity and excellent cross-species pharmacokinetic parameters and in vivo efficacy.
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Feb 2020
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I02-Macromolecular Crystallography
I04-1-Macromolecular Crystallography (fixed wavelength)
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Jason G.
Kettle
,
Rana
Anjum
,
Evan
Barry
,
Deepa
Bhavsar
,
Crystal
Brown
,
Scott
Boyd
,
Andrew
Campbell
,
Kristin
Goldberg
,
Michael
Grondine
,
Sylvie
Guichard
,
Christopher J.
Hardy
,
Tom
Hunt
,
Rhys D. O.
Jones
,
Xiuwei
Li
,
Olga
Moleva
,
Derek
Ogg
,
Ross C.
Overman
,
Martin J.
Packer
,
Stuart
Pearson
,
Marianne
Schimpl
,
Wenlin
Shao
,
Aaron
Smith
,
James M.
Smith
,
Darren
Stead
,
Steve
Stokes
,
Michael
Tucker
,
Yang
Ye
Diamond Proposal Number(s):
[12419, 14631]
Abstract: While the treatment of gastrointestinal stromal tumors (GISTs) has been revolutionized by the application of targeted tyrosine kinase inhibitors capable of inhibiting KIT-driven proliferation, diverse mutations to this kinase drive resistance to established therapies. Here we describe the identification of potent pan-KIT mutant kinase inhibitors that can be dosed without being limited by the tolerability issues seen with multitargeted agents. This effort focused on identification and optimization of an existing kinase scaffold through the use of structure-based design. Starting from a series of previously reported phenoxyquinazoline and quinoline based inhibitors of the tyrosine kinase PDGFRα, potency against a diverse panel of mutant KIT driven Ba/F3 cell lines was optimized, with a particular focus on reducing activity against a KDR driven cell model in order to limit the potential for hypertension commonly seen in second and third line GIST therapies. AZD3229 demonstrates potent single digit nM growth inhibition across a broad cell panel, with good margin to KDR-driven effects. Selectivity over KDR can be rationalized predominantly by the interaction of water molecules with the protein and ligand in the active site, and its kinome selectivity is similar to the best of the approved GIST agents. This compound demonstrates excellent cross-species pharmacokinetics, shows strong pharmacodynamic inhibition of target, and is active in several in vivo models of GIST.
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Sep 2018
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I03-Macromolecular Crystallography
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Jason G.
Kettle
,
Husam
Alwan
,
Michal
Bista
,
Jason
Breed
,
Nichola L.
Davies
,
Kay
Eckersley
,
Shaun
Fillery
,
Kevin M.
Foote
,
Louise
Goodwin
,
David R.
Jones
,
Helena
Käck
,
Alan
Lau
,
J. Willem M.
Nissink
,
Jon
Read
,
James S.
Scott
,
Ben
Taylor
,
Graeme
Walker
,
Lisa
Wissler
,
Marta
Wylot
Open Access
Abstract: Recent literature has claimed that inhibition of the enzyme MTH1 can eradicate cancer. MTH1 is one of the “housekeeping” enzymes that are responsible for hydrolyzing damaged nucleotides in cells and thus prevent them from being incorporated into DNA. We have developed orthogonal and chemically distinct tool compounds to those published in the literature to allow us to test the hypothesis that inhibition of MTH1 has wide applicability in the treatment of cancer. Here we present the work that led to the discovery of three structurally different series of MTH1 inhibitors with excellent potency, selectivity, and proven target engagement in cells. None of these compounds elicited the reported cellular phenotype, and additional siRNA and CRISPR experiments further support these observations. Critically, the difference between the responses of our highly selective inhibitors and published tool compounds suggests that the effect reported for the latter may be due to off-target cytotoxic effects. As a result, we conclude that the role of MTH1 in carcinogenesis and utility of its inhibition is yet to be established.
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Feb 2016
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Scott
Boyd
,
Joanna L.
Brookfield
,
Susan E.
Critchlow
,
Iain A.
Cumming
,
Nicola J.
Curtis
,
Judit
Debreczeni
,
Sébastien L.
Degorce
,
Craig
Donald
,
Nicola J.
Evans
,
Sam
Groombridge
,
Philip
Hopcroft
,
Neil P.
Jones
,
Jason G.
Kettle
,
Scott
Lamont
,
Hilary J.
Lewis
,
Philip
Macfaull
,
Sheila B.
Mcloughlin
,
Laurent J. M.
Rigoreau
,
James M.
Smith
,
Steve
St-Gallay
Abstract: A weak screening hit with suboptimal physicochemical properties was optimized against PFKFB3 kinase using critical structure-guided insights. The resulting compounds demonstrated high selectivity over related PFKFB isoforms and modulation of the target in a cellular context. A selected example demonstrated exposure in animals following oral dosing. Examples from this series may serve as useful probes to understand the emerging biology of this metabolic target.
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Apr 2015
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