Fig. 3.

Development of inhibitors targeting the lipid‐binding site of p38γ. (A) The three best druggable sites on p38γ are located using Druggable Site Prediction (DSP) method where FDA‐approved drug probes prefer to bind (Site 1 in red, Site 2 in blue, and Site 3 in green). The table at the bottom shows that 41% of FDA drug probes prefer to bind at the ATP‐binding site (Site 1, MaxGScore of −9.82 kcal·mol⁻¹), with 23% of FDA drug probes bound to Site 2, (MaxGScore of −8.9), the second‐preferentially druggable site on p38γ which is the lipid‐binding domain. Both Site 2 and Site 3 cover the lipid‐binding domain of p38γ. (B) An illustration of multiple steps to develop inhibitors bound to the lipid‐binding site of p38γ, which includes Docking of the NCI DTP compound library (270,000 compounds) to the lipid‐binding site of p38γ (PBD:1cm8, top left); 100 compounds were selected using virtual ligand screening (top right); 80 available compounds were ordered from NCI DTP for cytotoxicity assays; two compounds, CSH18 (NSC109833) and CSH71 (NSC381863) were selected due to their cytotoxicity against Hut78 CTCL cells, with IC₅₀ = 3.4 µm and 33 nm, respectively. As CSH18 is a speculated alkylator, we synthesized CSH18CN, which structure is depicted in the middle (Bottom).