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Instruments / Technical Area	Publication Details	Published
I04-Macromolecular Crystallography	ALK2 receptor kinase association with FKBP12.6 is structurally conserved with the ALK2-FKBP12 complex Eleanor Williams , Elise Riesebos , Georgina Kerr , Alex N. Bullock Biomedicines 9 DOI: 10.3390/biomedicines9020129 Diamond Proposal Number(s): [8421] Open Access Show Abstract ▼ Abstract: The immunophilin FKBP12 is a known inhibitor of type I BMP and TGF-β receptors that competes for binding with their substrate SMADs. FKBP12 and the close paralog FKBP12.6 additionally assemble with ryanodine receptors to control Ca2+ release. Binding of FKBP12.6 to BMP/TGF-β receptors has yet to be investigated, but appears plausible given its high sequence similarity to FKBP12. Here, we found that FKBP12.6 can assemble with BMP and TGF-β-family type I receptors, but not with type II receptors. Cellular immunoprecipitation confirmed similar binding of FKBP12 and FKBP12.6 to the BMP receptor ALK2 (ACVR1), a known target of mutations in the congenital syndrome fibrodysplasia ossificans progressiva (FOP), as well as the pediatric brain tumor diffuse intrinsic pontine glioma (DIPG). SEC-MALS analyses using purified proteins indicated a direct 1:1 interaction between FKBP12.6 and the receptor’s cytoplasmic domains. The 2.17 Å structure of this ALK2-FKBP12.6 complex bound to the inhibitor dorsomorphin showed FKBP12.6 binding to the GS domain of ALK2 in a manner equivalent to the FKBP12 complex, with ALK2 residues Phe198 and Leu199 extending into the FK506-binding pocket of FKBP12.6. These findings suggest a level of redundancy in FKBP-family regulation of BMP and TGF-β signaling.	Jan 2021
I03-Macromolecular Crystallography	Leveraging an open science drug discovery model to develop CNS penetrant ALK2 inhibitors for the treatment of diffuse intrinsic pontine glioma David Smil , Jong Fu Wong , Eleanor Williams , Roslin J. Adamson , Alison Howarth , David Mcleod , Ahmed Mamai , Soyoung Kim , Brian Wilson , Taira Kiyota , Ahmed Aman , Julie Owen , Gennady Poda , Kurumi Horiuchi , Ekaterina Kuznetsova , Haiching Ma , J. Nicole Hamblin , Sue Cramp , Owen Roberts , Aled M. Edwards , David Uehling , Rima Al-awar , Alex N. Bullock , Jeff O'meara , Methvin Isaac Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.0c01199 Show Abstract ▼ Abstract: There are currently no effective chemotherapeutic drugs approved for the treatment of diffuse intrinsic pontine glioma (DIPG), an aggressive pediatric cancer resident in the pons region of the brainstem. Radiation therapy is beneficial but not curative, with the condition being uniformly fatal. Analysis of the genomic landscape surrounding DIPG has revealed that activin receptor-like kinase-2 (ALK2) constitutes a potential target for therapeutic intervention given its dysregulation in the disease. We adopted an open science approach to develop a series of potent, selective, orally bioavailable, and brain penetrant ALK2 inhibitors based on lead compound LDN-214117. Modest structural changes to the C-3, C-4, and C-5 position substituents of the core pyridine ring afforded compounds M4K2009, M4K2117, and M4K2163, each with a superior potency, selectivity, and/or blood-brain barrier (BBB) penetration profile. Robust in vivo pharmacokinetic (PK) properties and tolerability mark these inhibitors as advanced pre-clinical compounds suitable for further development and evaluation in orthotopic models of DIPG.	Aug 2020
I03-Macromolecular Crystallography	Targeting ALK2: An open science approach to developing therapeutics for the treatment of diffuse intrinsic pontine glioma Deeba Ensan , David Smil , Carlos A. Zepeda-velázquez , Dimitrios Panagopoulos , Jong Fu Wong , Eleanor P. Williams , Roslin Adamson , Alex N. Bullock , Taira Kiyota , Ahmed Aman , Owen G. Roberts , Aled M. Edwards , Jeff A. O’meara , Methvin B. Isaac , Rima Al-awar Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.0c00395 Diamond Proposal Number(s): [19301] Show Abstract ▼ Abstract: Diffuse intrinsic pontine glioma is an aggressive pediatric cancer for which no effective chemotherapeutic drugs exist. Analysis of the genomic landscape of this disease has led to the identification of the serine/threonine kinase ALK2 as a potential target for therapeutic intervention. In this work, we adopted an open science approach to develop a series of potent type I inhibitors of ALK2 which are orally bio-available and brain-penetrant. Initial efforts resulted in the discovery of M4K2009, an analogue of the previously reported ALK2 inhibitor LDN-214117. Although highly selective for ALK2 over the TGF-βR1 receptor ALK5, M4K2009 is also moderately active against the hERG potassium channel. Varying the substituents of the trimethoxyphenyl moiety gave rise to an equipotent benzamide analogue M4K2149 with reduced off-target affinity for the ion channel. Additional modifications yielded 2-fluoro-6-methoxybenzamide derivatives (26a–c), which possess high inhibitory activity against ALK2, excellent selectivity, and superior pharmacokinetic profiles.	May 2020
I03-Macromolecular Crystallography	Mutant ACVR1 arrests glial cell differentiation to drive tumorigenesis in pediatric gliomas Jerome Fortin , Ruxiao Tian , Ida Zarrabi , Graham Hill , Eleanor Williams , Gonzalo Sanchez-duffhues , Midory Thorikay , Parameswaran Ramachandran , Robert Siddaway , Jong Fu Wong , Annette Wu , Lorraine N. Apuzzo , Jillian Haight , Annick You-ten , Bryan E. Snow , Andrew Wakeham , David J. Goldhamer , Daniel Schramek , Alex N. Bullock , Peter Ten Dijke , Cynthia Hawkins , Tak W. Mak Cancer Cell 37, 308 - 323.e12 DOI: 10.1016/j.ccell.2020.02.002 Diamond Proposal Number(s): [15433] Show Abstract ▼ Abstract: Diffuse intrinsic pontine gliomas (DIPGs) are aggressive pediatric brain tumors for which there is currently no effective treatment. Some of these tumors combine gain-of-function mutations in ACVR1, PIK3CA, and histone H3-encoding genes. The oncogenic mechanisms of action of ACVR1 mutations are currently unknown. Using mouse models, we demonstrate that Acvr1 G328V arrests the differentiation of oligodendroglial lineage cells, and cooperates with Hist1h3b K27M and Pik3ca H1047R to generate high-grade diffuse gliomas. Mechanistically, Acvr1 G328V upregulates transcription factors which control differentiation and DIPG cell fitness. Furthermore, we characterize E6201 as a dual inhibitor of ACVR1 and MEK1/2, and demonstrate its efficacy toward tumor cells in vivo. Collectively, our results describe an oncogenic mechanism of action for ACVR1 mutations, and suggest therapeutic strategies for DIPGs.	Mar 2020
I04-Macromolecular Crystallography	Development of macrocycle kinase inhibitors for ALK2 using Fibrodysplasia ossificans progressiva-derived endothelial cells Gonzalo Sánchez-duffhues , Eleanor Williams , Pascal Benderitter , Valeria Orlova , Michiel Van Wijhe , Amaya Garcia De Vinuesa , Georgina Kerr , Josselin Caradec , Kirsten Lodder , Hetty C. De Boer , Marie-josé Goumans , Elisabeth M. W. Eekhoff , Antonio Morales-piga , Javier Bachiller-corral , Pieter Koolwijk , Alex N. Bullock , Jan Hoflack , Peter Ten Dijke Jbmr Plus DOI: 10.1002/jbm4.10230 Diamond Proposal Number(s): [8421] Open Access Show Abstract ▼ Abstract: Fibrodysplasia ossificans progressiva (FOP) is an extremely rare congenital form of heterotopic ossification (HO), caused by heterozygous mutations in the Activin A type I receptor (ACVR1), that encodes the bone morphogenetic protein (BMP) type I receptor ALK2. These mutations enable ALK2 to induce downstream signaling in response to Activins, thereby turning them into bone inducing agents. To date there is no cure for FOP. The further development of FOP patient‐derived models may contribute to discover novel biomarkers and therapeutic approaches. Nevertheless, this has traditionally been a challenge, as biopsy sampling often triggers HO. We have characterized peripheral blood‐derived endothelial colony forming cells (ECFCs) from three independent FOP donors as a new model for FOP. FOP ECFCs are prone to undergo Endothelial‐to‐mesenchymal transition and exhibit increased ALK2 downstream signaling and subsequent osteogenic differentiation upon stimulation with Activin A. Moreover, we have identified a new class of small molecule macrocycles with potential activity against ALK2 kinase. Finally, using FOP ECFCs, we have selected OD36 and OD52 as potent inhibitors with excellent kinase selectivity profiles that potently antagonize mutant ALK2 signaling and osteogenic differentiation. We expect that these results will contribute to the development of novel ALK2 clinical candidates for the treatment of FOP.	Aug 2019
I02-Macromolecular Crystallography I03-Macromolecular Crystallography I04-Macromolecular Crystallography	Novel quinazolinone inhibitors of ALK2 flip between alternate binding modes: Structure–activity relationship, structural characterization, kinase profiling, and cellular proof of concept Liam Hudson , James Mui , Santiago Vázquez , Diana M. Carvalho , Eleanor Williams , Chris Jones , Alex N. Bullock , Swen Hoelder Journal Of Medicinal Chemistry DOI: 10.1021/acs.jmedchem.8b00782 Diamond Proposal Number(s): [10619] Open Access Show Abstract ▼ Abstract: Structure–activity relationship and crystallographic data revealed that quinazolinone-containing fragments flip between two distinct modes of binding to activin receptor-like kinase-2 (ALK2). We explored both binding modes to discover potent inhibitors and characterized the chemical modifications that triggered the flip in binding mode. We report kinase selectivity and demonstrate that compounds of this series modulate ALK2 in cancer cells. These inhibitors are attractive starting points for the discovery of more advanced ALK2 inhibitors.	Aug 2018
I03-Macromolecular Crystallography	Structural basis for the potent and selective binding of LDN-212854 to the BMP receptor kinase ALK2 Eleanor Williams , Alex N. Bullock Bone DOI: 10.1016/j.bone.2017.09.004 Diamond Proposal Number(s): [8421] Open Access Show Abstract ▼ Abstract: Individuals with the rare developmental disorder fibrodysplasia ossificans progressiva (FOP) experience disabling heterotopic ossification caused by a gain of function mutation in the intracellular region of the BMP type I receptor kinase ALK2, encoded by the gene ACVR1. Small molecule BMP type I receptor inhibitors that block this ossification in FOP mouse models have been derived from the pyrazolo[1,5-a]pyrimidine scaffold of dorsomorphin. While the first derivative LDN-193189 exhibited pan inhibition of BMP receptors, the more recent compound LDN-212854 has shown increased selectivity for ALK2. Here we solved the crystal structure of ALK2 in complex with LDN-212854 to define how its binding interactions compare to previously reported BMP and TGFβ receptor inhibitors. LDN-212854 bound to the kinase hinge region as a typical type I ATP-competitive inhibitor with a single hydrogen bond to ALK2 His286. Specificity arising from the 5-quinoline moiety was associated with a distinct pattern of water-mediated hydrogen bonds involving Lys235 and Glu248 in the inactive conformation favoured by ALK2. The structure of this complex provides a template for the design of future ALK2 inhibitors under development for the treatment of FOP and other related conditions of heterotopic ossification.	Sep 2017
I03-Macromolecular Crystallography	Small Molecules Dorsomorphin and LDN-193189 Inhibit Myostatin/GDF8 Signaling and Promote Functional Myoblast Differentiation Daniel Horbelt , Jan H. Boergermann , Apirat Chaikuad , Ivan Alfano , Eleanor Williams , Ilya Lukonin , Tobias Timmel , Alex N Bullock , Petra Knaus Journal Of Biological Chemistry DOI: 10.1074/jbc.M114.604397 PMID: 25368322 Diamond Proposal Number(s): [442] Open Access Show Abstract ▼ Abstract: GDF8, or myostatin, is a member of the TGF-β superfamily of secreted polypeptide growth factors. GDF8 is a potent negative regulator of myogenesis both in vivo and in vitro. We found that GDF8 signaling was inhibited by the small molecule ATP competitive inhibitors Dorsomorphin and LDN-193189. These compounds were previously shown to be potent inhibitors of BMP signaling by binding to the type BMP type I receptors ALK1/2/3/6. We present the crystal structure of the type II receptor ActRIIA with dorsomorphin, and demonstrate that dorsomorphin or LDN-193189 target GDF8 induced Smad2/3 signaling and repression of myogenic transcription factors. As a result, both inhibitors rescue myogenesis in myoblasts treated with GDF8. As revealed by quantitative live cell microscopy, treatment with dorsomorphin or LDN-193189 promoted the contractile activity of myotubular networks in vitro. We therefore suggest these inhibitors as suitable tools to promote functional myogenesis.	Nov 2014

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