The C-H — O hydrogen bond is so well established in structural biology today, that it’s been overlooked that the C-H — O hydrogen bond was first proposed by a woman, June Sutor, in a 1960’s Nature article.1  Her commentary was well ahead of its time, considering the limited crystallographic data in the early 60’s (the structure of insulin wasn’t solved until 1969 by Dorothy Hodgkin).2 Hydrogen bonds were then assumed to be linear (A-H···A’ between 150-180º), and the C-H — O hydrogen bonds proposed by Sutor are frequently nonlinear (C-H···A’ between 102-142º).  As Desiraju recounts in a 1996 article on the topic, “her suggestion was drowned in skepticism, if not outright hostility.”3  It took two decades for the concept to be finally revisited by Robin Taylor and Olga Kennard4.  This week, outstanding scientists Naomi Rajapaksa and Callie Bryan from Genentech describe their team’s work on IRAK4 inhibitors which bind via a C-H — O interaction (Figure 1) in a special ‘Women in Medicinal Chemistry’ issue of ACS Med. Chem. Lett.5

A C-H-O polarized C-H hydrogen bond to the kinase hinge
Figure 1. A crystal structure of a lead lactam bound to IRAK4 (PDB: 6UYA) shows a polarized C-H···O interaction between the pyrazolopyrimidine moiety to the hinge region. Modified from Ref. 5.

IRAK4 is a kinase that plays an important in multiple proinflammatory signaling pathways, and hence is a target for inflammatory diseases like lupus and rheumatoid arthritis.  The IRAK4 team explain that while they were able to obtain potent, orally bioavailable IRAK4 inhibitors such as dihydrobenzofuran 4,6 this older generation of compounds were moderately and variably potent in a human whole blood (HWB) assay for IL-6 and IFNα suppression (IC50s ~400 nM ± ~200 nM).  The team hypothesized that the whole blood assay issue might be specific to the dihydrobenzofuran scaffold, and thus examined targeting alternate scaffolds.  This exploration of dihydrobenzofuran alternatives led to the more efficient benzolactam scaffold present in 19.  Gratifyingly, not only did compound 19 have greater activity and less variability than original compound 4 in the human whole blood assay, it also showed significant activity with low variability in vivo.  See the article for more about this nice solution to an unexpected biological observation.

Summary of Genentech IRAK4 optimization and in vivo data
Figure 2. The search for a compound with improved human whole blood (HWB) activity to 4 reveals compound 19, which is more potent and has less variable activity in vitro. In an TLR7/8 agonist-induced mouse PD model, compound 19 also displays significant and dose-dependent activity in significant contrast to compound 4 despite matched compound exposure levels.

For more on recent advances in targeting kinases for the treatment of immunological disorders, see this very helpful review article also by the authors here.7

Happy hunting! Explore for more.

  1. Sutor, D. J. “The C-H … O Hydrogen Bond in Crystals.” Nature, 1962, 195, 68-69.
  2. Adams MJ, Blundell TL, Dodson EJ, Dodson GG, Vijayan M, Baker EN, Harding MM, Hodgkin D, Rimmer B, Sheat S. 1969. “Structure of rhombohedral 2-zinc insulin crystals.” Nature, 224, 3491-495.
  3. Desiraju, G. R. “The C-H···O Hydrogen Bond: Structural Implications and Supramolecular Design.” Acc. Chem. Res. 1996, 9, 441-449.
  4. Taylor, R. Kennard, O. “Crystallographic Evidence for the Existence of C-H···O, C-H···N, and C-H···Cl Hydrogen Bonds.” J. Am. Chem. Soc. 1982, 104, 5063-5070.
  5. Rajapaksa, N. et al. “Discovery of Potent Benzolactam IRAK4 Inhibitors with Robust in Vivo Activity.” ACS Med. Chem. Lett. 2019, doi: 10.1021/acsmedchemlett.9b00380
  6. Bryan, M. C. et al. “Development of Potent and Selective Pyrazolopyrimidine IRAK4 Inhibitors.” J. Med. Chem. 2019, 62, 6223-6240.
  7. Bryan, M. C. and Rajapaksa, N. S. “Kinase Inhibitors for the Treatment of Immunological Disorders: Recent Advances.” J. Med. Chem. 2018, 61, 9030-0958.