The January issue of J. Med. Chem is a bumper issue focussed on kinase inhibitors (January 27, 2022, Volume 65, Issue 2). Just about all of the papers are worthy of reading. It is likely you have already downloaded and seen it, but the review of small molecule kinase inhibitors looks to be the winner.

sunitinib bound

Each drug is well described, including synthesis and many 3D structures of substrate bound to protein. I chose sunitanib (Figure 8 above) as a picture, as this drug gave my father two years of extra life.

Small Molecule Kinase Inhibitor Drugs (1995–2021): Medical Indication, Pharmacology, and Synthesis

Cecilia C. Ayala-Aguilera, Teresa Valero, Álvaro Lorente-Macías, Daniel J. Baillache, Stephen Croke, and Asier Unciti-Broceta*

J. Med. Chem. 2022, 65, 2, 1047–1131


Of the other papers we thought we would give a shout-out, is perhaps one of the ‘underdogs’ of this collection. In late LO, as candidate selection approaches, and in-vitro secondary screening is taking place, an issue can arise if pregnane X
receptor (PXR) activation occurs. This in turn can activate a range of CYP450 metabolising enzymes and account for the poor pharmacokinetic profiles. This paper describes a successful effort to remove PXR binding through a measured rational approach. The solution is also quite a good isostere from a tert-butyl group too. One to keep in case if you ever hit this problem.

tbutyl to morpholine

Structure-Based and Knowledge-Informed Design of B-Raf Inhibitors Devoid of Deleterious PXR Binding

Melanie Schneider, Vanessa Delfosse, Muriel Gelin, Marina Grimaldi, Meritxell Granell, Laurène Heriaud, Jean-Luc Pons, Martin Cohen Gonsaud*, Patrick Balaguer*, William Bourguet*, and Gilles Labess*

J. Med. Chem. 2022, 65, 2, 1552–1566