title: Fragment-based ligand design of novel potent inhibitors of tankyrases.
abstract: Tankyrases constitute potential drug targets for cancer and myelin-degrading diseases. We have applied a structure- and biophysics-driven fragment-based ligand design strategy to discover a novel family of potent inhibitors for human tankyrases. Biophysical screening based on a thermal shift assay identified highly efficient fragments binding in the nicotinamide-binding site, a local hot spot for fragment binding. Evolution of the fragment hit 4-methyl-1,2-dihydroquinolin-2-one (2) along its 7-vector yields dramatic affinity improvements in the first cycle of expansion. A crystal structure of 7-(2-fluorophenyl)-4-methylquinolin-2(1H)-one (11) reveals that the nonplanar compound extends with its fluorine atom into a pocket, which coincides with a region of the active site where structural differences are seen between tankyrases and other poly(ADP-ribose) polymerase (PARP) family members. A further cycle of optimization yielded compounds with affinities and IC50 values in the low nanomolar range and with good solubility, PARP selectivity, and ligand efficiency.
authors.affiliation: School of Biological Sciences, Nanyang Technological University, Lab 07-01, 61 Biopolis Drive (Proteos), Singapore 138673. andreas.larsson@ntu.edu.sg
authors.forename: E Andreas
authors.initials: EA
authors.lastname: Larsson
authors.forename: Anna
authors.initials: A
authors.lastname: Jansson
authors.forename: Fui Mee
authors.initials: FM
authors.lastname: Ng
authors.forename: Siew Wen
authors.initials: SW
authors.lastname: Then
authors.forename: Resmi
authors.initials: R
authors.lastname: Panicker
authors.forename: Boping
authors.initials: B
authors.lastname: Liu
authors.forename: Kanda
authors.initials: K
authors.lastname: Sangthongpitag
authors.forename: Vishal
authors.initials: V
authors.lastname: Pendharkar
authors.forename: Shi Jing
authors.initials: SJ
authors.lastname: Tai
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Hill
authors.forename: Chen
authors.initials: C
authors.lastname: Dan
authors.forename: Soo Yei
authors.initials: SY
authors.lastname: Ho
authors.forename: Wei Wen
authors.initials: WW
authors.lastname: Cheong
authors.forename: Anders
authors.initials: A
authors.lastname: Poulsen
authors.forename: Stephanie
authors.initials: S
authors.lastname: Blanchard
authors.forename: Grace Ruiting
authors.initials: GR
authors.lastname: Lin
authors.forename: Jenefer
authors.initials: J
authors.lastname: Alam
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Keller
authors.forename: Pär
authors.initials: P
authors.lastname: Nordlund
mesh_terms: D018360:Crystallography, X-Ray; D016208:Databases, Factual; D004355:Drug Stability; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry; D012995:Solubility; D013329:Structure-Activity Relationship; D038501:Tankyrases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013816:Thermodynamics
chemical_list: D008024:Ligands; D011804:Quinolines; C437334:TNKS2 protein, human; D038501:Tankyrases