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Instruments / Technical Area	Publication Details	Published
I03-Macromolecular Crystallography	Identification of novel small molecule ligands for JAK2 pseudokinase domain Anniina T. Virtanen , Teemu Haikarainen , Parthasarathy Sampathkumar , Maaria Palmroth , Sanna Liukkonen , Jianping Liu , Natalia Nekhotiaeva , Stevan R. Hubbard , Olli Silvennoinen Pharmaceuticals 16 DOI: 10.3390/ph16010075 Diamond Proposal Number(s): [26794] Open Access Show Abstract ▼ Abstract: Hyperactive mutation V617F in the JAK2 regulatory pseudokinase domain (JH2) is prevalent in patients with myeloproliferative neoplasms. Here, we identified novel small molecules that target JH2 of JAK2 V617F and characterized binding via biochemical and structural approaches. Screening of 107,600 small molecules resulted in identification of 55 binders to the ATP-binding pocket of recombinant JAK2 JH2 V617F protein at a low hit rate of 0.05%, which indicates unique structural characteristics of the JAK2 JH2 ATP-binding pocket. Selected hits and structural analogs were further assessed for binding to JH2 and JH1 (kinase) domains of JAK family members (JAK1-3, TYK2) and for effects on MPN model cell viability. Crystal structures were determined with JAK2 JH2 wild-type and V617F. The JH2-selective binders were identified in diaminotriazole, diaminotriazine, and phenylpyrazolo-pyrimidone chemical entities, but they showed low-affinity, and no inhibition of MPN cells was detected, while compounds binding to both JAK2 JH1 and JH2 domains inhibited MPN cell viability. X-ray crystal structures of protein-ligand complexes indicated generally similar binding modes between the ligands and V617F or wild-type JAK2. Ligands of JAK2 JH2 V617F are applicable as probes in JAK-STAT research, and SAR optimization combined with structural insights may yield higher-affinity inhibitors with biological activity.	Jan 2023
I03-Macromolecular Crystallography I04-1-Macromolecular Crystallography (fixed wavelength)	Structure-activity relationships of 2-arylquinazolin-4-ones as highly selective and potent inhibitors of the tankyrases Amit Nathubhai , Teemu Haikarainen , Penelope C. Hayward , Silvia Muñoz-Descalzo , Andrew S. Thompson , Matthew D. Lloyd , Lari Lehtiö , Michael D. Threadgill European Journal Of Medicinal Chemistry 118, 316 - 327 DOI: 10.1016/j.ejmech.2016.04.041 Show Abstract ▼ Abstract: Tankyrases (TNKSs), members of the PARP (Poly(ADP-ribose)polymerases) superfamily of enzymes, have gained interest as therapeutic drug targets, especially as they are involved in the regulation of Wnt signalling. A series of 2-arylquinazolin-4-ones with varying substituents at the 8-position was synthesised. An 8-methyl group (compared to 8-H, 8-OMe, 8-OH), together with a 4′-hydrophobic or electron-withdrawing group, provided the most potency and selectivity towards TNKSs. Co-crystal structures of selected compounds with TNKS-2 revealed that the protein around the 8-position is more hydrophobic in TNKS-2 compared to PARP-1/2, rationalising the selectivity. The NAD+-binding site contains a hydrophobic cavity which accommodates the 2-aryl group; in TNKS-2, this has a tunnel to the exterior but the cavity is closed in PARP-1. 8-Methyl-2-(4-trifluoromethylphenyl)quinazolin-4-one was identified as a potent and selective inhibitor of TNKSs and Wnt signalling. This compound and analogues could serve as molecular probes to study proliferative signalling and for development of inhibitors of TNKSs as drugs.	Aug 2016
I04-Macromolecular Crystallography	Para substituted 2-phenyl-3,4-dihydroquinazolin-4-ones as potent and selective tankyrase inhibitors Teemu Haikarainen , Jarkko Koivunen , Mohit Narwal , Harikanth Venkannagari , Ezeogo Obaji , Päivi Joensuu , Taina Pihlajaniemi , Lari Lehtiö Chemmedchem DOI: 10.1002/cmdc.201300337 PMID: 24130191 Diamond Proposal Number(s): [8030] Show Abstract ▼ Abstract: Human tankyrases are attractive drug targets, especially for the treatment of cancer. We identified a SET of highly potent tankyrase inhibitors based on a 2-phenyl-3,4-dihydroquinazolin-4-one scaffold. Substitutions at the para position of the scaffold′s phenyl group were evaluated as a strategy to increase potency and improve selectivity. The best compounds displayed single-digit nanomolar potencies, and profiling against several human diphtheria-toxin-like ADP-ribosyltransferases revealed that a subset of these compounds are highly selective tankyrase inhibitors. The compounds also effectively inhibit Wnt signaling in HEK293 cells. The binding mode of all inhibitors was studied by protein X-ray crystallography. This allowed us to establish a structural basis for the development of highly potent and selective tankyrase inhibitors based on the 2-phenyl-3,4-dihydroquinazolin-4-one scaffold and outline a rational approach to the modification of other inhibitor scaffolds that bind to the nicotinamide site of the catalytic domain.	Oct 2013

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