I03-Macromolecular Crystallography
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Robert L.
Hudkins
,
Eric
Allen
,
Samhita
Iyer
,
Alexandra
Balcer
,
Melissa
Neal
,
Qing
Ye
,
Marc
Rideout
,
Caleb B.
Frye
,
Kirk J.
Nelson
,
Isaac D.
Hoffman
,
Jacqueline H.
Starrett
,
Todd
Harris
,
Ronald V.
Swanson
,
Daniel C.
Bensen
Diamond Proposal Number(s):
[41212]
Abstract: Genetic alterations in FGFR2 drive multiple malignancies, most notably intrahepatic cholangiocarcinoma, where they occur in ∼10–15% of patients. While approved pan-FGFR inhibitors provide clinical benefit, their durability is limited by acquired, often polyclonal, on-target resistance mutations affecting key regions of the FGFR2 kinase domain, including the gatekeeper residue (V565), molecular brake residues (N550, E566, K642), and other key variants. These liabilities motivate the development of next-generation inhibitors. Given FGFR2-associated toxicities and the need for subtype selectivity, FGFR4 inhibition was prioritized as a selectivity determinant, while sparing FGFR1 was considered less critical. Guided by structure-based drug design, a reversible aminopyrimidine screening hit was optimized into a novel covalent inhibitor series active against FGFR2 wild-type and clinically relevant resistance mutations. An advanced lead 13 showed favorable potency, ADME properties, and demonstrated proof-of-concept in vivo efficacy in an FGFR2-amplified xenograft model comparable with the standard of care.
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Apr 2026
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I04-Macromolecular Crystallography
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Ludivine
Moine
,
Wei
Hu
,
Alison
Davis
,
Emanuele
Perola
,
Jian
Guo
,
Kevin
Barvian
,
Yeon Sook
Choi
,
Alexandra
Grassian
,
Joseph L.
Kim
,
Omar K.
Ahmad
,
Thomas A.
Dineen
Open Access
Abstract: Gastrointestinal stromal tumor (GIST) is the most common type of sarcoma of the gastrointestinal tract, with approximately 5000 new cases annually in the USA. Approximately 80% of GIST cases are driven by activating mutations in KIT in exon 9 or 11. Resistance to present therapies like imatinib often arises from secondary KIT mutations, especially V654A (exon 13), which is the most frequent resistance mutation. Tyrosine kinase inhibitors (TKIs) currently approved for GIST can cause dose-limiting side effects due to off-target inhibition of other kinases. Herein, we report the discovery and optimization of BLU-654 (compound 18), a highly potent and kinome-sparing KIT V654A inhibitor. Preclinical efficacy studies demonstrated its prolonged antitumor activity in a KIT V654A cell-derived xenograft mouse model. BLU-654 offers a potent and selective profile suitable for combination therapy for KIT-mutant GIST patients.
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Mar 2026
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labSAXS-Offline SAXS and Sample Environment Development
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Diamond Proposal Number(s):
[40382]
Open Access
Abstract: The vast majority of small-molecule active pharmaceutical ingredients (APIs) are formulated in the crystalline state, for reasons including thermodynamic stability, ease of purification and characterisation, and better control over polymorphism. However, the selective crystallisation of polymorphic APIs provides a significant hurdle to overcome, especially in the case of API co-crystals. Herein we report a series of low-molecular-weight organogels (LMWGs) which can be used to selectively crystallise APIs. In solution, these LMWGs (2–10 mg mL−1) self-assemble through hydrogen bonding to form stable gels which feature nano-structured morphologies. When utilised as crystallisation media, these LMWGs can influence crystal growth, as evidenced by the discovery of two novel 1[thin space (1/6-em)]:[thin space (1/6-em)]1 co-crystals of chlorzoxazone with nicotinamide and chlorzoxazone with isonicotinamide. This work highlights the potential of LMWGs as another means of controlling API crystallisation.
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Mar 2026
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B23-Circular Dichroism
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Diamond Proposal Number(s):
[37842]
Open Access
Abstract: Chiral materials that manipulate circularly polarised light have burgeoning applications across optoelectronics, sensing and information encoding, yet the functionality of organic molecular materials is often limited by their relatively low dissymmetry factors (gabs/lum < 10−2), including towards the near infrared (λ > 700 nm). An effective strategy to amplifying gabs/lum is to optimise the chiral arrangement of chromophores, with single crystals providing intrinsic molecular ordering. Herein, we quantify the circular dichroism and circularly polarised luminescence of single crystals of a chiral L-valinol bis-perylene diimide macrocycle by Mueller–Matrix polarimetry and circularly polarised luminescence microscopy, as required for the analysis of such anisotropic materials. Through this, we see that organic crystals are valuable for understanding how supramolecular structure can be used to modify the sign, strength and energy of the chiroptical signal. Indeed, by tuning the macrocycle's π–π stacking interactions, our materials deliver strong chiroptical properties (gabs/lum > 10−2), including circularly polarised luminescence into the near infrared (λ = 780 nm).
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Feb 2026
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I04-Macromolecular Crystallography
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Qiangqiang
Wei
,
Ashley J.
Taylor
,
Nagaraju
Miriyala
,
Mahesh A.
Barmade
,
Zachary O.
Gentry
,
Jordan
Anderson-Daniels
,
Kevin B.
Teuscher
,
Mackenzie M.
Crow
,
Chideraa
Apakama
,
Taylor M.
South
,
Tyson A.
Rietz
,
Kangsa
Amporndanai
,
Jason
Phan
,
John L.
Sensintaffar
,
Mark
Denison
,
Taekyu
Lee
,
Stephen W.
Fesik
Open Access
Abstract: The papain-like protease (PLPro) plays a key role in SARS-CoV-2 replication and represents a promising target for the development of new antiviral therapies. Previous efforts to develop fragment-derived inhibitors of PLPro led to the identification of a novel class of spiro[chromane-2,4′-piperidin]-4-one inhibitors exemplified by lead compound 7. High-resolution covalent cocrystal structures and molecular dynamics simulations were utilized to guide the development of a series of low-nanomolar irreversible PLPro inhibitors, with lead compound 45 demonstrating strong enzymatic inhibition (IC50 = 0.059 μM at T = 60 min) and antiviral activity in A549 cells (EC50 = 2.1 μM at 48 hpi). This novel class of inhibitors represents a promising avenue for the development of therapeutics to overcome the potential of drug-resistant viral strains and future coronavirus outbreaks.
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Feb 2026
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I04-Macromolecular Crystallography
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Fabiana Izidro A. L.
Layng
,
Huiyu
Ren
,
Nicole A.
Bakas
,
Dhanya R.
Panickar
,
Lester J.
Lambert
,
Maria
Celeridad
,
Jiaqian
Wu
,
Laurent
De Backer
,
Preeti
Chandrachud
,
Allison S.
Limpert
,
Mitchell
Vamos
,
Apirat
Chaikuad
,
Betsaida B.
Verdugo
,
Patrick M.
Hagan
,
Sonja N.
Brun
,
Lutz
Tautz
,
Stefan
Knapp
,
Reuben J.
Shaw
,
Guy S.
Salvesen
,
Douglas J.
Sheffler
,
Nicholas D. P.
Cosford
Abstract: Autophagy inhibition represents a promising therapeutic approach for the management of various cancers including nonsmall cell lung cancer (NSCLC). We previously reported SBP-7455, a dual inhibitor of unc-51-like kinase 1 (ULK1) and its homologue ULK2 and described its effects on triple-negative breast cancer (TNBC) cells. Herein we report the design, synthesis, and characterization of SBP-5147 and SBP-7501, two new dual ULK1/2 inhibitors that are cytotoxic against NSCLC cells, inhibit autophagic flux in A549 cells, and present greater oral exposure than SBP-7455 at a lower dose. In addition, SBP-5147 effectively modulates autophagy and increases the expression of major histocompatibility complex (MHC) class I in NSCLC cells, which may support the rationale for ULK1/2 inhibition as a strategy to overcome resistance to immunotherapy. Together these data support the use of ULK inhibitors as part of a cancer treatment strategy, either as a single agent or in combination with current therapies.
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Feb 2026
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I03-Macromolecular Crystallography
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Open Access
Abstract: Aromatic polyketides from Actinobacteria are structurally complex bioactive natural products with significant therapeutic potential, whose biosynthesis involves polyketide chain assembly, keto reduction, cyclization, and aromatization. This is followed by pathway-specific enzymatic tailoring steps, occasionally including rare oxidative rearrangements of the carbon skeleton, as exemplified by the rishirilides. In this study, we investigate RslO9, a flavin-dependent tailoring key enzyme of rishirilide biosynthesis, previously hypothesized to facilitate a lactone-forming Baeyer–Villiger oxidation of the rishirilide naphthoquinone core and subsequent intramolecular aldol condensation. Through detailed investigation of RslO9’s mechanism, structural features, and substrate scope, we unexpectedly found that the naphthoquinone moiety of the non-natural substrate lapachol undergoes hydroxylation followed by a benzilic acid rearrangement, producing the Hooker intermediate–a hallmark of the intricate Hooker oxidation. Our data support a similar alkyl migration mechanism for RslO9’s native substrate, upending its prior classification as a Baeyer–Villiger monooxygenase and challenging the proposed role of related enzymes while also providing a novel framework for exploring their catalytic roles.
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Jan 2026
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I03-Macromolecular Crystallography
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Chongxun
Ge
,
Dazhi
Feng
,
Song
Shi
,
Xuzhen
Tang
,
Yaqi
Cui
,
Song
Liu
,
Yunyue
Wang
,
Shuangtian
Tang
,
Xinnan
Li
,
Xianqiang
Sun
,
Daopeng
Yuan
,
Jinyi
Xu
,
Hu
He
,
Hong
Yao
Abstract: DNA polymerase theta (Polθ), which mediates microhomology-mediated end joining (MMEJ) in homologous recombination-deficient (HRD) cancers, has recently emerged as a compelling synthetic lethal target. Combining Polθ inhibition with PARP inhibitors represents a promising strategy to overcome PARP inhibitor resistance. Here, we present the discovery of SY-589, a highly potent (ATPase IC50 = 2.29 nM), selective (selectivity index >1800), and orally bioavailable (F = 107%) Polθ helicase inhibitor, which exhibits robust antitumor efficacy in HRD tumors in vitro (CTG IC50 = 2.71 nM). Notably, SY-589 synergized strongly with the PARP inhibitor Olaparib in vitro (Loewe score >20) and in vivo (TGI = 109%), enhancing antitumor effects while permitting reduced Olaparib dosing. Overall, SY-589 is a promising candidate of Polθ inhibitor and has been positioned as a rational combination partner with PARP inhibitors, aiming to overcome PARP inhibitor resistance and mitigate their dose-limiting toxicities.
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Jan 2026
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I04-Macromolecular Crystallography
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Qiangqiang
Wei
,
Ashley J.
Taylor
,
Mahesh Angadrao
Barmade
,
Kevin B.
Teuscher
,
Somanath
Chowdhury
,
Chideraa
Apakama
,
Jordan
Anderson-Daniels
,
Zhu
Yongqing
,
David C.
Schultz
,
Tyson A.
Rietz
,
Taylor M.
South
,
Mackenzie M.
Crow
,
Bin
Zhao
,
Kangsa
Amporndanai
,
John L.
Sensintaffar
,
Jason
Phan
,
Sara
Cherry
,
Mark
Denison
,
Taekyu
Lee
,
Stephen W.
Fesik
Diamond Proposal Number(s):
[42696]
Open Access
Abstract: SARS-CoV-2 papain-like protease (PLPro) plays a key role in viral replication and the host immune response and is a promising target for developing new antiviral treatments. We previously reported a fragment-based screen to identify hits that bind to SARS-CoV-2 PLPro. Here, we describe the discovery of potent PLPro inhibitors by optimizing one of these hits via extensive medicinal chemistry guided by multiple X-ray structures of cocomplexes. Lead compound 46 is shown to bind to the S3 and S4 pockets with nanomolar affinity (0.4 μM) and exhibits robust cellular activity and resistance to mutation. This novel class of PLPro inhibitors can potentially be used as a starting point for the development of inhibitors to combat the emergence of drug-resistant viral strains and future coronavirus outbreaks.
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Jan 2026
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I19-Small Molecule Single Crystal Diffraction
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Diamond Proposal Number(s):
[40576]
Open Access
Abstract: Photocatalysis offers a promising approach for renewable energy conversion and storage, but short lifetimes of charge-separated states in photocatalysts due to charge recombination limit its utility. Here we report an organic molecule with an acceptor–donor–acceptor configuration that can self assemble into highly crystalline nanoparticles. Transient absorption spectroscopy reveals that these crystalline assemblies can induce an ultra-long-lived charge-separated state of up to 1.2 s, attributed to initial symmetry-breaking charge separation, followed by charge hopping across closely packed molecules. These self-assembled nanoparticles have an impressive photocatalytic H2 evolution rate of 126 mmol g−1 h−1 with an external quantum efficiency of 12% at 550 nm under optimized conditions. This system shows a remarkable stability with 220 million turnover numbers (per particle) over the 77 h of operation. These findings suggest that rational design of organic molecules and their aggregates is vital for improving light-induced charge separation and for developing highly efficient, stable and scalable organic photocatalysts.
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Jan 2026
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