I04-Macromolecular Crystallography
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Silvia
Bonomo
,
Michael D.
Lainchbury
,
Floriane
Gibault
,
Sharan K.
Bagal
,
J. Henry
Blackwell
,
Jason
Breed
,
Gavin W.
Collie
,
Maxime
Couturier
,
Coura
Diène
,
Paolo
Di Fruscia
,
Sean
Gray
,
Craig
Hughes
,
Dhadchayini
Jeyaharan
,
Jason G.
Kettle
,
Alexander G.
Milbradt
,
Sarah
Northall
,
Katherine
Peters
,
Christopher
J. Stubbs
,
Elizabeth
Underwood
,
Yunhua
Chen
,
Haie
Hao
Abstract: SOS1 is one of the key regulators of KRAS where it catalyzes the GTP-to-GDP turnover required for KRAS activation. Inhibition of the SOS1::KRAS interaction is an attractive strategy to modulate abnormal KRAS activation, which is responsible for several malignancies. In this work, we performed a virtual screening campaign on the AstraZeneca compound collection with Heavy Atom Count between 21 and 26 and identified two novel and efficient binders of SOS1 which fulfill the minimal pharmacophoric requirements disclosed in known compounds. Subsequently, structure- and knowledge-based approaches were applied to develop these binders into functional inhibitors of SOS1.
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Sep 2025
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I04-Macromolecular Crystallography
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Simon C. C.
Lucas
,
Alexander G.
Milbradt
,
Jason
Breed
,
Erwin
De Genst
,
Anne
Jackson
,
Alisa
Solovyeva
,
Bryony
Ackroyd
,
Matthias R.
Bauer
,
Juntai
Liu
,
David
Longmire
,
Dušan
Petrović
,
Emma L.
Rivers
,
Christopher
Stubbs
,
Poppy
Winlow
,
Sana
Bazzaz
,
Paige
Dickson
,
Diana
Gikunju
,
Marie-Aude
Guié
,
John P.
Guilinger
,
Christopher D.
Hupp
,
Rachael
Jetson
,
Anthony D.
Keefe
,
Katherine
Nugai
,
John T. S.
Yeoman
,
Ying
Zhang
,
Xian
Feng
,
Dequan
Yu
,
Christopher
Phillips
Diamond Proposal Number(s):
[20015]
Abstract: STIP1 homology and U-box containing protein 1 (STUB1), also known as the C-terminus of Hsc70-interacting protein (CHIP), is an E3 ligase that plays a crucial role in removal of misfolded proteins via Hsc70. A DEL screen was run against CHIP to identify small-molecule binders. Two hits were identified that were confirmed by biochemical and biophysical techniques, including 2D NMR. X-ray crystal structures were obtained, which revealed binding to the peptide binding site. Fragment-based deconstruction indicated that hit 2 was a suitable starting point for optimization. During the optimization, an unexpected rearrangement of an oxadiazole from an array hit led to the exploration of an amide vector. This resulted in the discovery of compound 5, which is the most potent small-molecule ligand for CHIP identified to date and a suitable starting point for further optimization into a tool molecule or PROTAC warhead.
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Aug 2025
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I03-Macromolecular Crystallography
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Jeffrey A.
Boerth
,
Marianne
Schimpl
,
Simon C. C.
Lucas
,
Jingwen
Zhang
,
Erin L.
Code
,
Kevin J.
Embrey
,
Philip B.
Rawlins
,
Haixia
Wang
,
R. Ian
Storer
,
Paolo
Di Fruscia
,
Jennifer E.
Nelson
,
Alexander G.
Milbradt
,
Ulf
Börjesson
,
Andrea
Gohlke
,
Victoria
Korboukh
,
Ariamala
Gopalsamy
Diamond Proposal Number(s):
[20015]
Abstract: Suppression of oncogenic gene expression is an effective strategy for the treatment of cancer. The SWI/SNF (SWItch/Sucrose Non-Fermentable) complex plays an important role in regulating gene activation or repression, and its dysregulation has been linked to aberrant transcription activity in many types of cancer. Targeting the subunits of this complex, such as SMARCA2, SMARCA4, and PBRM1, which are part of the bromodomain family VIII, has significant therapeutic potential. Herein we report the discovery of pyrimidoindolones as a novel series of bromodomain family VIII binders identified through an NMR-based fragment screen. These binders have been optimized to achieve sub-μM affinity for the family VIII proteins SMARCA2, SMARCA4, and PRBM1, with promising physicochemical properties.
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May 2025
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I03-Macromolecular Crystallography
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Joanna L.
Chen
,
Joey L.
Methot
,
Matthew J.
Mitcheltree
,
Andrew
Musacchio
,
Emily B.
Corcoran
,
Guo
Feng
,
Alfred
Lammens
,
Klaus
Maskos
,
Rachel L.
Palte
,
Meredith M.
Rickard
,
Karin M.
Otte
,
My S.
Mansueto
,
Sriraman
Venkat
,
Christopher
Sondey
,
Maren
Thomsen
,
Charles A.
Lesburg
,
Xavier
Fradera
,
Matthew J.
Fell
,
Erin F.
Dimauro
,
Phieng
Siliphaivanh
Abstract: Receptor-interacting protein kinase 1 (RIPK1) plays an essential role in necroptosis, a form of inflammatory, caspase-independent, programmed cell death. Allosteric inhibitors of RIPK1 have been shown to block necroptotic cell death and thus may offer potential therapeutic opportunities across a range of infectious, autoimmune, and neurodegenerative diseases. We report the structure-informed discovery of a novel series of bridged benzoazepine amides as part of our efforts to develop a CNS-penetrant small-molecule inhibitor of RIPK1 with a low projected oral human dose.
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May 2025
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I04-Macromolecular Crystallography
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Simon C. C.
Lucas
,
Yong
Xu
,
Sarah
Hewitt
,
Gavin W.
Collie
,
Lucia
Fusani
,
Ganesh
Kadamur
,
Thomas E.
Hadfield
,
Nancy
Su
,
Caroline
Truman
,
Sylvain
Demanze
,
Haie
Hao
,
Christopher
Phillips
Abstract: Most ligands for the Von Hippel–Lindau tumor suppressor (VHL) bind at the HIF-1α binding site. Ligands that bind to allosteric sites on VHL could be highly valuable for the field of protein degradation, therefore, a covalent hit identification campaign was run targeting Cys77 on VHL. Hit 2 bound selectively to Cys77 on VHL and did not alkylate the reactive Cys89 on Elongin B. It showed time- and concentration-dependent labeling, with a kinact/KI of 0.30 M–1 s–1, and does not affect binding at the HIF-1α site. This hit ligand was optimized to afford compound 15 which showed improved potency and labeling of VHL. An X-ray structure of a close analogue was determined revealing the compound binding in a shallow groove on the surface of VHL. These are the first small molecules that bind covalently to an allosteric site on VHL and provide a suitable starting point for further optimization.
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Mar 2025
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I04-Macromolecular Crystallography
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Marco
Paolino
,
Giusy
Tassone
,
Paolo
Governa
,
Mario
Saletti
,
Matteo
Lami
,
Riccardo
Carletti
,
Filippo
Sacchetta
,
Cecilia
Pozzi
,
Maurizio
Orlandini
,
Fabrizio
Manetti
,
Massimo
Olivucci
,
Andrea
Cappelli
Diamond Proposal Number(s):
[21741, 29907]
Abstract: The use of Targeted Covalent Inhibitors (TCIs) is an expanding strategy for the development of innovative drugs. It is driven by two fundamental steps: (1) recognition of the target site by the molecule and (2) establishment of the covalent interaction by its reactive group. The development of new TCIs depends on the development of new warheads. Here, we propose the use of Morita–Baylis–Hillman adducts (MBHAs) to covalently bind Lys strategically placed inside a lipophilic pocket. A human cellular retinoic acid binding protein II mutant (M2) was selected as a test bench for a library of 19 MBHAs. The noncovalent interaction step was investigated by molecular docking studies, while experimentally the entire library was incubated with M2 and crystallized to confirm covalent binding with the target lysine. The results, rationalized through covalent docking analysis, support our hypothesis of MBHAs as reactive scaffolds for the design of lysine-TCIs.
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Mar 2025
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I03-Macromolecular Crystallography
I04-1-Macromolecular Crystallography (fixed wavelength)
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Ross P.
Hryczanek
,
Andrew S.
Hackett
,
Paul
Rowland
,
Chun-Wa
Chung
,
Máire A.
Convery
,
Duncan S.
Holmes
,
Jonathan P.
Hutchinson
,
Semra
Kitchen
,
Justyna
Korczynska
,
Robert P.
Law
,
Jonathan D.
Lea
,
John
Liddle
,
Richard
Lonsdale
,
Margarete
Neu
,
Leng
Nickels
,
Alex
Phillipou
,
James E.
Rowedder
,
Jessica L.
Schneck
,
Paul
Scott-Stevens
,
Hester
Sheehan
,
Chloe L.
Tayler
,
Ioannis
Temponeras
,
Christopher P.
Tinworth
,
Ann L.
Walker
,
Justyna
Wojno-Picon
,
Robert J.
Young
,
David M.
Lindsay
,
Efstratios
Stratikos
Diamond Proposal Number(s):
[20024]
Open Access
Abstract: Endoplasmic reticulum aminopeptidase 1 (ERAP1) cleaves the N-terminal amino acids of peptides, which can then bind onto major histocompatibility class I (MHC-I) molecules for presentation onto the cell surface, driving the activation of adaptive immune responses. In cancer, overtrimming of mature antigenic peptides can reduce cytotoxic T-cell responses, and ERAP1 can generate self-antigenic peptides which contribute to autoimmune cellular responses. Therefore, modulation of ERAP1 activity has potential therapeutic indications for cancer immunotherapy and in autoimmune disease. Herein we describe the hit-to-lead optimization of a series of cyclohexyl acid ERAP1 inhibitors, found by X-ray crystallography to bind at an allosteric regulatory site. Structure-based drug design enabled a >1,000-fold increase in ERAP1 enzymatic and cellular activity, resulting in potent and selective tool molecules. For lead compound 7, rat pharmacokinetic properties showed moderate unbound clearance and oral bioavailability, thus highlighting the promise of the series for further optimization.
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Dec 2024
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I04-Macromolecular Crystallography
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Diamond Proposal Number(s):
[25108]
Open Access
Abstract: In this Letter, we present a small series of novel bacterial topoisomerase inhibitors (NTBIs) that exhibit both potent inhibition of Mycobacterium tuberculosis DNA gyrase and potent antimycobacterial activity. The disclosed crystal structure of M. tuberculosis DNA gyrase in complex with DNA and compound 5 from this NBTI series reveals the binding mode of an NBTI in the GyrA binding pocket and confirms the presence and importance of halogen bonding for the excellent on-target potency. In addition, we have shown that compound 5 is a promising M. tuberculosis DNA gyrase inhibitor, with an IC50 for M. tuberculosis gyrase of 0.096 μM, and it has potent activity against M. tuberculosis, with an IC50 of 0.165 μM.
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Nov 2024
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I24-Microfocus Macromolecular Crystallography
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Open Access
Abstract: Galectin-8 contains two different carbohydrate recognition domains (CRDs). Selective inhibitors for at least one CRD are desirable for galectin-8 biology studies and potentially for pharmacological purposes. Structure-guided design led to the discovery of potent and selective glycomimetic–heterocycle hybrid ligands, with a 4-(p-bromophenyl)phthalazinone derivative displaying a 34 μM Kd for galectin-8N (N-terminal CRD), no binding to galectin-8C (C-terminal CRD), -1, -3, -4N, -7, -9C, or -9N, and >40-fold selectivity over galectin-4C. Selectivity was achieved with the halogenated 4-phenylphthalazinone moiety occupying a galectin-8N-specific sub-pocket. A 1.30 Å resolution X-ray structure revealed the phthalazinone moiety stacking with Arg45 and the 4-bromophenyl moiety stacking both Arg59 and Tyr141 of galectin-8N. Physicochemical and in vitro ADME studies revealed a desirable LogD, which also translated to good passive permeability. The chemical, microsome, and plasma stability support these compounds as promising tool compounds and candidates for hit-to-lead optimization.
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Aug 2024
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I04-Macromolecular Crystallography
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Frances M.
Bashore
,
Sophia M.
Min
,
Xiangrong
Chen
,
Stefanie
Howell
,
Caroline H.
Rinderle
,
Gabriel
Morel
,
Josie A.
Silvaroli
,
Carrow I.
Wells
,
Bruce A.
Bunnell
,
David H.
Drewry
,
Navjot S.
Pabla
,
Sila K.
Ultanir
,
Alex N.
Bullock
,
Alison D.
Axtman
Open Access
Abstract: Acylaminoindazole-based inhibitors of CDKL2 were identified via analyses of cell-free binding and selectivity data. Compound 9 was selected as a CDKL2 chemical probe based on its potent inhibition of CDKL2 enzymatic activity, engagement of CDKL2 in cells, and excellent kinome-wide selectivity, especially when used in cells. Compound 16 was designed as a negative control to be used alongside compound 9 in experiments to interrogate CDKL2-mediated biology. A solved cocrystal structure of compound 9 bound to CDKL2 highlighted key interactions it makes within its ATP-binding site. Inhibition of downstream phosphorylation of EB2, a CDKL2 substrate, in rat primary neurons provided evidence that engagement of CDKL2 by compound 9 in cells resulted in inhibition of its activity. When used at relevant concentrations, compound 9 does not impact the viability of rat primary neurons or certain breast cancer cells nor elicit consistent changes in the expression of proteins involved in epithelial–mesenchymal transition.
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Aug 2024
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