Fragment-to-Lead Successes in 2019

In this blogpost, I want to highlight the excellent work by Jahnke and collaborators. For the past 5 years, they have published an annual perspective covering fragment-to-lead success stories from the previous year. Very helpfully, their work includes a table detailing the hit fragment(s) and lead molecule, together with key experimental results and parameters.

In addition to providing an exhaustive list of fragment-to-lead developments, advances in technologies and trends in fragment elaboration are discussed. This year, they highlighted increased interest in covalent fragments (a recent topical example of the use of covalent fragments), the use of FBDD to modulate protein-protein interactions (further reading on FBDD for PPIs), as well new technologies such as MiniFrags (ultrasmall fragments) and FragLites (halogenated compounds containing paired hydrogen-bonding motifs).

If you’re interested in FBDD, take a look!

  • Fragment hit (PDB ID 6OOY)
  • Lead molecule (PDB ID 6OP0)
Example of a successful fragment-to-lead optimisation (Entry 18 in Table 1, Jahnke et al., 2020). O’Connell et al., 2019 developed a potent inhibitor of tumour necrosis factor (TNF) improving the potency over 1000-fold from a Kd of 22μM to 0.013μM with no impact on ligand efficiency.

Citation:
Jahnke W., Erlanson D. A., de Esch I. J. P., Johnson C. N., Mortenson P. N., Ochi Y., and Urushima T., Fragment-to-Lead Medicinal Chemistry Publications in 2019, J. Med. Chem. 2020 63 (24), 15494-15507, DOI: 10.1021/acs.jmedchem.0c01608

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