Discovery of a Potent and Selective Fragment-like Inhibitor of Methyllysine Reader Protein Spindlin 1 (SPIN1).
Yan XiongHolger GreschikCatrine JohanssonLudwig SeifertJohannes BacherKwang-Su ParkNicolas BabaultMichael MartiniVincent FaganFengling LiIrene ChauThomas ChristottDavid DilworthDalia Barsyte-LovejoyMasoud VedadiCheryl H ArrowsmithPaul E BrennanOleg FedorovManfred JungGillian FarnieJing LiuUdo OppermannRoland SchüleJian JinPublished in: Journal of medicinal chemistry (2019)
By screening an epigenetic compound library, we identified that UNC0638, a highly potent inhibitor of the histone methyltransferases G9a and GLP, was a weak inhibitor of SPIN1 (spindlin 1), a methyllysine reader protein. Our optimization of this weak hit resulted in the discovery of a potent, selective, and cell-active SPIN1 inhibitor, compound 3 (MS31). Compound 3 potently inhibited binding of trimethyllysine-containing peptides to SPIN1, displayed high binding affinity, was highly selective for SPIN1 over other epigenetic readers and writers, directly engaged SPIN1 in cells, and was not toxic to nontumorigenic cells. The crystal structure of the SPIN1-compound 3 complex indicated that it selectively binds tudor domain II of SPIN1. We also designed a structurally similar but inactive compound 4 (MS31N) as a negative control. Our results have demonstrated for the first time that potent, selective, and cell-active fragment-like inhibitors can be generated by targeting a single tudor domain.
Keyphrases
- room temperature
- density functional theory
- single molecule
- transition metal
- dna methylation
- induced apoptosis
- mass spectrometry
- small molecule
- molecular dynamics
- cell cycle arrest
- stem cells
- anti inflammatory
- high throughput
- ms ms
- amino acid
- cell proliferation
- protein protein
- ionic liquid
- cell death
- endoplasmic reticulum stress
- oxidative stress
- transcription factor
- capillary electrophoresis