Case Study 1
Rapid development of Tomivosertib (eFT508), a first-in-class drug candidate, via FBDD
A rational structure-based design approach balances the needs of high potency and exquisite selectivity with facile chemistry and desirable physiochemical properties. Crystallography at SBD enabled our client, eFFECTOR Therapeutics, to rapidly develop mitogen-activating kinase (MNK) inhibitors. SBD crystal structures of MNK with fragments, leads, and clinical candidate bound MNK were critical during the design cycle[2-9]. Compound eFT508, a very potent and selective dual MNK1/2 inhibitor was developed based on 30 crystal structures and required synthesis fewer than 100 compounds. The project was initiated in 2013, when MNK was a relatively new drug target with few publications. An IND was filed less than two years later, in 2015, and eFT508 is currently in multiple phase II clinical trials.
- Structure-based Design of Pyridone–Aminal eFT508 Targeting Dysregulated Translation by Selective Mitogen-activated Protein Kinase Interacting Kinases 1 and 2 (MNK1/2) Inhibition. J Med. Chem., 61, 3516-40.
- MNK PDB 6CJ5: https://www.rcsb.org/structure/6CJ5
- MNK PDB 6CJE: https://www.rcsb.org/structure/6CJE
- MNK PDB 6CJH: https://www.rcsb.org/structure/6CJH
- MNK PDB 6CJW: https://www.rcsb.org/structure/6CJW
- MNK PDB 6CJY: https://www.rcsb.org/structure/6CJY
- MNK PDB 6CK3: https://www.rcsb.org/structure/6CK3
- MNK PDB 6CK6: https://www.rcsb.org/structure/6CK6
- MNK PDB 6CKI: https://www.rcsb.org/structure/6CKI
- Clinical progress of eFT508 https://effector.com/pipeline/