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Instruments / Technical Area	Publication Details	Published
I03-Macromolecular Crystallography	Discovery of 6-fluoro-5-{4-[(5-fluoro-2-methyl-3-oxo-3,4-dihydroquinoxalin-6-yl)methyl]piperazin-1-yl}-N-methylpyridine-2-carboxamide (AZD9574): A CNS-penetrant, PARP1-selective inhibitor 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 Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.4c01725 Diamond Proposal Number(s): [20015] Show Abstract ▼ 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.	Dec 2024
I04-1-Macromolecular Crystallography (fixed wavelength)	Fragment-based discovery of a novel, brain penetrant, orally active HDAC2 inhibitor Emiliano Tamanini , Shin Miyamura , Ildiko M. Buck , Benjamin D. Cons , Lee Dawson , Charlotte East , Takashi Futamura , Shintaro Goto , Charlotte Griffiths-Jones , Tetsuya Hashimoto , Tom D. Heightman , Shunpei Ishikawa , Hideki Ito , Yosuke Kaneko , Tatsuya Kawato , Kazumi Kondo , Naoki Kurihara , James M. Mccarthy , Yukiko Mori , Tsuyoshi Nagase , Yuichiro Nakaishi , Judith Reeks , Akimasa Sato , Patrick Schöpf , Kuninori Tai , Taichi Tamai , Dominic Tisi , Alison J.-A. Woolford Acs Medicinal Chemistry Letters DOI: 10.1021/acsmedchemlett.2c00272 Show Abstract ▼ Abstract: Fragment-based ligand discovery was successfully applied to histone deacetylase HDAC2. In addition to the anticipated hydroxamic acid- and benzamide-based fragment screening hits, a low affinity (∼1 mM) α-amino-amide zinc binding fragment was identified, as well as fragments binding to other regions of the catalytic site. This alternative zinc-binding fragment was further optimized, guided by the structural information from protein–ligand complex X-ray structures, into a sub-μM, brain penetrant, HDAC2 inhibitor (17) capable of modulating histone acetylation levels in vivo.	Sep 2022
I03-Macromolecular Crystallography I04-1-Macromolecular Crystallography (fixed wavelength)	Discovery of 5-{4-[(7-Ethyl-6-oxo-5,6-dihydro-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl}- N -methylpyridine-2-carboxamide (AZD5305): A PARP1–DNA Trapper with High Selectivity for PARP1 over PARP2 and Other PARPs 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 Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.1c01012 Diamond Proposal Number(s): [14631, 17180, 20015] Show Abstract ▼ 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.	Sep 2021
I02-Macromolecular Crystallography	Quantitation of ERK1/2 inhibitor cellular target occupancies with a reversible slow off-rate probe Honorine Lebraud , Olga Surova , Aurélie Courtin , Marc O'Reilly , Chiara R. Valenzano , Pär Nordlund , Tom D. Heightman Chemical Science 9, 8608 - 8618 DOI: 10.1039/C8SC02754D Open Access Show Abstract ▼ Abstract: Target engagement is a key concept in drug discovery and its direct measurement can provide a quantitative understanding of drug efficacy and/or toxicity. Failure to demonstrate target occupancy in relevant cells and tissues has been recognised as a contributing factor to the low success rate of clinical drug development. Several techniques are emerging to quantify target engagement in cells; however, in situ measurements remain challenging, mainly due to technical limitations. Here, we report the development of a non-covalent clickable probe, based on SCH772984, a slow off-rate ERK1/2 inhibitor, which enabled efficient pull down of ERK1/2 protein via click reaction with tetrazine tagged agarose beads. This was used in a competition setting to measure relative target occupancy by selected ERK1/2 inhibitors. As a reference we used the cellular thermal shift assay, a label-free biophysical assay relying solely on ligand-induced thermodynamic stabilization of proteins. To validate the EC50 values measured by both methods, the results were compared with IC50 data for the phosphorylation of RSK, a downstream substrate of ERK1/2 used as a functional biomarker of ERK1/2 inhibition. We showed that a slow off-rate reversible probe can be used to efficiently pull down cellular proteins, significantly extending the potential of the approach beyond the need for covalent or photoaffinity warheads.	Nov 2018
I02-Macromolecular Crystallography	Fragment-based discovery of a potent, orally bioavailable inhibitor which modulates the phosphorylation and catalytic activity of ERK1/2 Tom D. Heightman , Valerio Berdini , Hannah Braithwaite , Ildiko Maria Buck , Megan Cassidy , Juan Castro , Aurelie Courtin , James E. H. Day , Charlotte East , Lynsey Fazal , Brent Graham , Charlotte M. Griffiths-Jones , John F. Lyons , Vanessa Martins , Sandra Muench , Joanne M. Munck , David Norton , Marc O'Reilly , Nick Palmer , Puja Pathuri , Michael Reader , David C. Rees , Sharna J. Rich , Caroline Richardson , Harpreet Saini , Neil T. Thompson , Nicola G. Wallis , Hugh Walton , Nicola E. Wilsher , Alison J.-A. Woolford , Michael Cooke , David Cousin , Stuart Onions , Jonathan Shannon , John Watts , Christopher W. Murray Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.8b00421 Show Abstract ▼ Abstract: Aberrant activation of the MAPK pathway drives cell proliferation in multiple cancers. Inhibitors of BRAF and MEK kinases are approved for the treatment of BRAF mutant melanoma, but resistance frequently emerges, often mediated by increased signalling through ERK1/2. Here we describe the fragment based generation of ERK1/2 inhibitors which block catalytic phosphorylation of downstream substrates such as RSK but also modulate phosphorylation of ERK1/2 by MEK without directly inhibiting MEK. X-ray crystallographic and biophysical fragment screening followed by structure-guided optimization and growth from the hinge into a pocket proximal to the C-α helix afforded highly potent ERK1/2 inhibitors with excellent kinome selectivity. In BRAF mutant cells the lead compound suppresses pRSK and pERK levels and inhibits proliferation at low nanomolar concentrations. The lead exhibits tumor regression upon oral dosing in BRAF mutant xenograft models, providing a promising basis for further optimization towards clinical pERK1/2 modulating ERK1/2 inhibitors.	May 2018
I03-Macromolecular Crystallography I04-Macromolecular Crystallography	Structure of the epigenetic oncogene MMSET and inhibition by N-alkyl sinefungin derivatives Dominic Tisi , Elisabetta Chiarparin , Emiliano Tamanini , Puja Pathuri , Joseph E. Coyle , Adam Hold , Finn P. Holding , Nader Amin , Agnes C. L. Martin , Sharna J. Rich , Valerio Berdini , Jeff Yon , Paul Acklam , Rosemary Burke , Ludovic Drouin , Jenny E. Harmer , Fiona Jeganathan , Rob Van Montfort , Yvette Newbatt , Marcello Tortorici , Maura Westlake , Amy Wood , Swen Hoelder , Tom D. Heightman Acs Chemical Biology 11, 3093 - 3105 DOI: 10.1021/acschembio.6b00308 Show Abstract ▼ Abstract: The members of the NSD subfamily of lysine methyl transferases are compelling oncology targets due to the recent characterization of gain-of-function mutations and translocations in several hematological cancers. To date, these proteins have proven intractable to small molecule inhibition. Here, we present initial efforts to identify inhibitors of MMSET (aka NSD2 or WHSC1) using solution phase and crystal structural methods. On the basis of 2D NMR experiments comparing NSD1 and MMSET structural mobility, we designed an MMSET construct with five point mutations in the N-terminal helix of its SET domain for crystallization experiments and elucidated the structure of the mutant MMSET SET domain at 2.1 Å resolution. Both NSD1 and MMSET crystal systems proved resistant to soaking or cocrystallography with inhibitors. However, use of the close homologue SETD2 as a structural surrogate supported the design and characterization of N-alkyl sinefungin derivatives, which showed low micromolar inhibition against both SETD2 and MMSET.	Nov 2016
I04-1-Macromolecular Crystallography (fixed wavelength) I04-Macromolecular Crystallography	A series of potent CREBBP bromodomain ligands reveals an induced-fit pocket stabilized by a cation–π interaction Timothy P. C. Rooney , Panagis Filippakopoulos , Oleg Fedorov , Sarah Picaud , Wilian A. Cortopassi , Duncan A. Hay , Sarah Martin , Anthony Tumber , Catherine M. Rogers , Martin Philpott , Minghua Wang , Amber L. Thompson , Tom D. Heightman , David C. Pryde , Andrew Cook , Robert S. Paton , Susanne Müller , Stefan Knapp , Paul E. Brennan , Stuart J. Conway Angewandte Chemie International Edition 53 (24), 6126 - 6130 DOI: 10.1002/anie.201402750 PMID: 24821300 Diamond Proposal Number(s): [8421] Open Access Show Abstract ▼ Abstract: The benzoxazinone and dihydroquinoxalinone fragments were employed as novel acetyl lysine mimics in the development of CREBBP bromodomain ligands. While the benzoxazinone series showed low affinity for the CREBBP bromodomain, expansion of the dihydroquinoxalinone series resulted in the first potent inhibitors of a bromodomain outside the BET family. Structural and computational studies reveal that an internal hydrogen bond stabilizes the protein-bound conformation of the dihydroquinoxalinone series. The side chain of this series binds in an induced-fit pocket forming a cation–? interaction with R1173 of CREBBP. The most potent compound inhibits binding of CREBBP to chromatin in U2OS cells.	Jun 2014
I02-Macromolecular Crystallography	Inhibition of histone demethylases by 4-carboxy-2,2′-bipyridyl compounds Kai-Hsuan Chang , Oliver N, F. King , Antony Tumber , Esther C. Y. Woon , Tom D. Heightman , Michael A. Mcdonough , Christopher J. Schofield , Nathan R. Rose Chemmedchem 6 (5), 759 - 764 DOI: 10.1002/cmdc.201100026 PMID: 21412984 Show Abstract ▼ Abstract: Exploiting epigenetics: 2-Oxoglutarate (2OG)-dependent histone lysine demethylases, such as JMJD2E, are potential therapeutic targets in a range of diseases. Through structure–activity relationship studies and analyses, we identified a potent 4-carboxy-2,2′-bipyridyl compound, which inhibits JMJD2E with an IC50 value of 110 nM, representing a 66-fold improvement over the lead compound. These bipyridyl derivatives bind in the 2-oxoglutarate binding site.	Mar 2011
I04-Macromolecular Crystallography	Quantitative high-throughput screening identifies 8-hydroxyquinolines as cell-active histone demethylase inhibitors Oliver N. F. King , Xuan Shirley Li , Masaaki Sakurai , Akane Kawamura , Nathan R. Rose , Stanley S. Ng , Amy M. Quinn , Ganesha Rai , Bryan Mott , Paul Beswick , Robert Klose , Udo Oppermann , Ajit Jadhav , Tom Heightman , David J. Maloney , Christopher J. Schofield , Anton Simeonov Plos One DOI: 10.1371/journal.pone.0015535 PMID: 21124847 Open Access Show Abstract ▼ Abstract: Small molecule modulators of epigenetic processes are currently sought as basic probes for biochemical mechanisms, and as starting points for development of therapeutic agents. N (epsilon)-Methylation of lysine residues on histone tails is one of a number of post-translational modifications that together enable transcriptional regulation. Histone lysine demethylases antagonize the action of histone methyltransferases in a site- and methylation state-specific manner. N (epsilon)-Methyllysine demethylases that use 2-oxoglutarate as co-factor are associated with diverse human diseases, including cancer, inflammation and X-linked mental retardation; they are proposed as targets for the therapeutic modulation of transcription. There are few reports on the identification of templates that are amenable to development as potent inhibitors in vivo and large diverse collections have yet to be exploited for the discovery of demethylase inhibitors.	Nov 2010

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